Benzothiophene compounds, intermediates, compositions, and methods

ABSTRACT

A method for alleviating the symptoms of post-menopausal syndrome comprising administering to a woman in need thereof an effective amount of a compound of formula I wherein R1a is -H or -OR7a in which R7a is -H or a hydroxy protecting group; R2a is -H, halo, or -OR8a in which R8a is -H or a hydroxy protecting group; R3 is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino; n is 2 or 3; and Z is -O- or -S-; or a pharmaceutically acceptable salt thereof.

This application is a divisional of application Ser. No. 08/554,223,filed Nov. 3, 1995, now U.S. Pat. No. 5,865,360, which is acontinuation-in-part of application Ser. No. 08/467,444, filed Jun. 6,1995, which is a divisional of application Ser. No. 08/396,401, filedFeb. 28, 1995, now U.S. Pat. No. 5,510,357.

FIELD OF THE INVENTION

This invention relates to the fields of pharmaceutical and organicchemistry and provides novel benzothiophene compounds which are usefulfor the treatment of the various medical indications associated withpost-menopausal syndrome, and uterine fibroid disease, endometriosis,and aortal smooth muscle cell proliferation. The present inventionfurther relates to intermediate compounds useful for preparing thepharmaceutically active compounds of the present invention, andpharmaceutical compositions.

BACKGROUND OF THE INVENTION

"Post-menopausal syndrome" is a term used to describe variouspathological conditions which frequently affect women who have enteredinto or completed the physiological metamorphosis known as menopause.Although numerous pathologies are contemplated by the use of this term,three major effects of post-menopausal syndrome are the source of thegreatest long-term medical concern: osteoporosis, cardiovascular effectssuch as hyperlipidemia, and estrogen-dependent cancer, particularlybreast and uterine cancer.

Osteoporosis describes a group of diseases which arise from diverseetiologies, but which are characterized by the net loss of bone mass perunit volume. The consequence of this loss of bone mass and resultingbone fracture is the failure of the skeleton to provide adequatestructural support for the body. One of the most common types ofosteoporosis is that associated with menopause. Most women lose fromabout 20% to about 60% of the bone mass in the trabecular compartment ofthe bone within 3 to 6 years after the cessation of menses. This rapidloss is generally associated with an increase of bone resorption andformation. However, the resorptive cycle is more dominant and the resultis a net loss of bone mass. Osteoporosis is a common and serious diseaseamong post-menopausal women.

There are an estimated 25 million women in the United States, alone, whoare afflicted with this disease. The results of osteoporosis arepersonally harmful and also account for a large economic loss due itschronicity and the need for extensive and long term support(hospitalization and nursing home care) from the disease sequelae. Thisis especially true in more elderly patients. Additionally, althoughosteoporosis is not generally thought of as a life threateningcondition, a 20% to 30% mortality rate is related with hip fractures inelderly women. A large percentage of this mortality rate can be directlyassociated with post-menopausal osteoporosis.

The most vulnerable tissue in the bone to the effects of post-menopausalosteoporosis is the trabecular bone. This tissue is often referred to asspongy or cancellous bone and is particularly concentrated near the endsof the bone (near the joints) and in the vertebrae of the spine. Thetrabecular tissue is characterized by small osteoid structures whichinterconnect with each other, as well as the more solid and densecortical tissue which makes up the outer surface and central shaft ofthe bone. This inter-connected network of trabeculae gives lateralsupport to the outer cortical structure and is critical to thebiomechanical strength of the overall structure. In post-menopausalosteoporosis, it is, primarily, the net resorption and loss of thetrabeculae which leads to the failure and fracture of bone. In light ofthe loss of the trabeculae in post-menopausal women, it is notsurprising that the most common fractures are those associated withbones which are highly dependent on trabecular support, e.g., thevertebrae, the neck of the weight bearing bones such as the femur andthe fore-arm. Indeed, hip fracture, collies fractures, and vertebralcrush fractures are hall-marks of post-menopausal osteoporosis.

At this time, the only generally accepted method for treatment ofpost-menopausal osteoporosis is estrogen replacement therapy. Althoughtherapy is generally successful, patient compliance with the therapy islow primarily because estrogen treatment frequently produces undesirableside effects.

Throughout premenopausal time, most women have less incidence ofcardiovascular disease than age-matched men. Following menopause,however, the rate of cardiovascular disease in women slowly increases tomatch the rate seen in men. This loss of protection has been linked tothe loss of estrogen and, in particular, to the loss of estrogen'sability to regulate the levels of serum lipids. The nature of estrogen'sability to regulate serum lipids is not well understood, but evidence todate indicates that estrogen can upregulate the low density lipid (LDL)receptors in the liver to remove excess cholesterol. Additionally,estrogen appears to have some effect on the biosynthesis of cholesterol,and other beneficial effects on cardiovascular health.

It has been reported in the literature that post-menopausal women havingestrogen replacement therapy have a return of serum lipid levels toconcentrations to those of the pre-menopausal state. Thus, estrogenwould appear to be a reasonable treatment for this condition. However,the side-effects of estrogen replacement therapy are not acceptable tomany women, thus limiting the use of this therapy. An ideal therapy forthis condition would be an agent which would regulate the serum lipidlevel as does estrogen, but would be devoid of the side-effects andrisks associated with estrogen therapy.

The third major pathology associated with post-menopausal syndrome isestrogen-dependent breast cancer and, to a lesser extent,estrogen-dependent cancers of other organs, particularly the uterus.Although such neoplasms are not solely limited to a post-menopausalwomen, they are more prevalent in the older, post-menopausal population.Current chemotherapy of these cancers has relied heavily on the use ofanti-estrogen compounds such as, for example, tamoxifen. Although suchmixed agonist-antagonists have beneficial effects in the treatment ofthese cancers, and the estrogenic side-effects are tolerable in acutelife-threatening situations, they are not ideal. For example, theseagents may have stimulatory effects on certain cancer cell populationsin the uterus due to their estrogenic (agonist) properties and they may,therefore, be contraproductive in some cases. A better therapy for thetreatment of these cancers would be an agent which is an anti-estrogencompound having negligible or no estrogen agonist properties onreproductive tissues.

In response to the clear need for new pharmaceutical agents which arecapable of alleviating the symptoms of, inter alia, post-menopausalsyndrome, the present invention provides new benzothiophene compounds,pharmaceutical compositions thereof, and methods of using such compoundsfor the treatment of post-menopausal syndrome and other estrogen-relatedpathological conditions such as those mentioned below.

Uterine fibrosis (uterine fibroid disease) is an old and ever presentclinical problem which goes under a variety of names, including uterinefibroid disease, uterine hypertrophy, uterine lieomyomata, myometrialhypertrophy, fibrosis uteri, and fibrotic metritis. Essentially, uterinefibrosis is a condition where there is an inappropriate deposition offibroid tissue on the wall of the uterus.

This condition is a cause of dysmenorrhea and infertility in women. Theexact cause of this condition is poorly understood but evidence suggeststhat it is an inappropriate response of fibroid tissue to estrogen. Sucha condition has been produced in rabbits by daily administrations ofestrogen for 3 months. In guinea pigs, the condition has been producedby daily administration of estrogen for four months. Further, in rats,estrogen causes similar hypertrophy.

The most common treatment of uterine fibrosis involves surgicalprocedures both costly and sometimes a source of complications such asthe formation of abdominal adhesions and infections. In some patients,initial surgery is only a temporary treatment and the fibroids regrow.In those cases a hysterectomy is performed which effectively ends thefibroids but also the reproductive life of the patient. Also,gonadotropin releasing hormone antagonists may be administered, yettheir use is tempered by the fact they can lead to osteoporosis. Thus,there exists a need for new methods for treating uterine fibrosis, andthe methods of the present invention satisfy that need.

Endometriosis is a condition of severe dysmenorrhea, which isaccompanied by severe pain, bleeding into the endometrial masses orperitoneal cavity and often leads to infertility. The cause of thesymptoms of this condition appear to be ectopic endometrial growthswhich respond inappropriately to normal hormonal control and are locatedin inappropriate tissues. Because of the inappropriate locations forendometrial growth, the tissue seems to initiate local inflammatory-likeresponses causing macrophage infiltration and a cascade of eventsleading to initiation of the painful response. The exact etiology ofthis disease is not well understood and its treatment by hormonaltherapy is diverse, poorly defined, and marked by numerous unwanted andperhaps dangerous side effects.

One of the treatments for this disease is the use of low dose estrogento suppress endometrial growth through a negative feedback effect oncentral gonadotropin release and subsequent ovarian production ofestrogen; however, it is sometimes necessary to use continuous estrogento control the symptoms. This use of estrogen can often lead toundesirable side effects and even the risk of endometrial cancer.

Another treatment consists of continuous administration of progestinswhich induces amenorrhea and by suppressing ovarian estrogen productioncan cause regressions of the endometrial growths. The use of chronicprogestin therapy is often accompanied by the unpleasant CNS sideeffects of progestins and often leads to infertility due to suppressionof ovarian function.

A third treatment consists of the administration of weak androgens,which are effective in controlling the endometriosis; however, theyinduce severe masculinizing effects. Several of these treatments forendometriosis have also been implicated in causing a mild degree of boneloss with continued therapy. Therefore, new methods of treatingendometriosis are desirable.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I ##STR2## whereinR¹ is --H, --OH, --O(C₁ -C₄ alkyl), --OCOC₆ H₅, --OCO(C₁ -C₆ alkyl), or--OSO₂ (C₂ -C₆ alkyl);

R² is --H, --OH, --O(C₁ -C₄ alkyl), --OCOC₆ H₅, --OCO(C₁ -C₆ alkyl),--OSO₂ (C₂ -C₆ alkyl) or halo;

R³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl,dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino,diisopropylamino, or 1-hexamethyleneimino;

n is 2 or 3; and

z is --O-- or --S--;

or a pharmaceutically acceptable salt thereof.

Further provided by the present invention are the following intermediatecompounds which are useful for preparing pharmaceutically activecompounds of the present invention, some of which are alsopharmaceutically active: ##STR3## wherein R^(1a) is --H or --OR⁷ inwhich R⁷ is a hydroxy protecting group;

R^(2a) is --H, halo, or --OR⁸ in which R⁸ is a hydroxy protecting group;

R³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl,dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diisopropylamino,or 1-hexamethyleneimino;

R⁶ is --H or a hydroxy protecting group which can be selectivelyremoved;

R⁹ is a leaving group;

R¹¹ is non-existent or ═O;

n is 2 or 3; and

Z is --O-- or --S--;

or a pharmaceutically acceptable salt thereof.

Also provided is a process for preparing compounds of the formula##STR4## wherein R^(1a) is --H or --OR^(7a) in which R^(7a) is --H or ahydroxy protecting group;

R^(2a) is --H, halo, or --OR^(8a) in which R^(8a) is --H or a hydroxyprotecting group;

R³ is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyrrolidinyl,dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino,diisopropylamino, or 1-hexamethyleneimino;

n is 2 or 3; and

Z is --O-- or --S--;

or a pharmaceutically acceptable salt thereof, comprising

a) oxidizing the sulfur atom of a formula IV compound ##STR5## whereinR^(1a) and R^(2a) are as previously defined; and

R⁹ is a leaving group;

b) reacting the product of step a), a compound of formula XIV ##STR6##with a nucleophilic group of the formula ##STR7## wherein R¹² is --OH or--SH; c) reducing the product of step b), a compound of formula XVI##STR8## to provide a compound of the formula ##STR9## d) optionallyremoving the R^(1a) and/or R^(2a) hydroxy protecting groups, whenpresent, of the product of step c); and

e) optionally forming a salt of the product of step c) or step d).

The present invention further relates to pharmaceutical compositionscontaining compounds of formula I, optionally containing estrogen orprogestin, and the use of such compounds, alone, or in combination withestrogen or progestin, for alleviating the symptoms of post-menopausalsyndrome, particularly osteoporosis, cardiovascular related pathologicalconditions, and estrogen-dependent cancer. As used herein, the termestrogen includes steroidal compounds having estrogenic activity suchas, for example, 17b-estradiol, estrone, conjugated estrogen(Premarin®), equine estrogen 17b-ethynyl estradiol, and the like. Asused herein, the term "progestin" includes compounds havingprogestational activity such as, for example, progesterone,norethylnodrel, nongestrel, megestrol acetate, norethindrone, and thelike.

The compounds of the present invention also are useful for inhibitinguterine fibroid disease and endometriosis in women, and aortal smoothmuscle cell proliferation, particularly restenosis, in humans.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention includes compounds of formula I##STR10## wherein R¹ is --H, --OH, --O(C₁ -C₄ alkyl), --OCOC₆ H₅,--OCO(C₁ -C₆ alkyl), or --OSO₂ (C₂ -C₆ alkyl);

R² is --H, --OH, --O(C₁ -C₄ alkyl), --OCOC₆ H₅, --OCO(C₁ -C₆ alkyl),--OSO₂ (C₂ -C₆ alkyl), or halo;

R³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl,dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino,diisopropylamino, or 1-hexamethyleneimino;

n is 2 or 3; and

z is --O-- or --S--;

or a pharmaceutically acceptable salt thereof.

General terms used in the description of compounds herein described beartheir usual meanings. For example, "C₁ -C₆ alkyl" refers to straight orbranched aliphatic chains of 1 to 6 carbon atoms including moieties suchas methyl, ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl,hexyl, isohexyl, and the like. Similarly, the term "C₁ -C₄ alkoxy"represents a C₁ -C₄ alkyl group attached through an oxygen molecule andinclude moieties such as, for example, methoxy, ethoxy, n-propoxy,isopropoxy, and the like.

The starting material for one route for preparing compounds of formula Iof the present invention, compounds of formula III, are preparedessentially as described by C. D. Jones in U.S. Pat. Nos. 4,418,068, and4,133,814, each of which is herein incorporated by reference. FormulaIII has the structure ##STR11## wherein R⁷ and R^(2a) are as definedabove.

The R⁷ and R⁸ hydroxy protecting groups are moieties which generally arenot found in the final, therapeutically active compounds of formula I,but which are intentionally introduced during a portion of the syntheticprocess to protect a group which otherwise might react in the course ofchemical manipulations, and is then removed at a later stage of thesynthesis. Since compounds bearing such protecting groups are ofimportance primarily as chemical intermediates (although somederivatives also exhibit biological activity), their precise structureis not critical. Numerous reactions for the formation, removal, andpossibly, reformation of such protecting groups are described in anumber of standard works including, for example, Protective Groups inOrganic Chemistry, Plenum Press (London and New York, 1973); Green, T.W., Protective Groups in Organic Synthesis, Wiley (New York, 1981); andThe Peptides, Vol. I, Schrooder and Lubke, Academic Press, (London andNew York, 1965).

Representative hydroxy protecting groups include, for example, --C₁ -C₄alkyl, --C₁ -C₄ alkoxy, --CO--(C₁ -C₆ alkyl), --SO₂ --(C₄ -C₆ alkyl),and --CO--Ar in which Ar is benzyl or optionally substituted phenyl. Theterm "substituted phenyl" refers to a phenyl group having one or moresubstituents selected from the group consisting of C₁ -C₄ alkyl, C₁ -C₄alkoxy, hydroxy, nitro, halo, and tri(chloro or fluoro) methyl. The term"halo" refers to bromo, chloro, fluoro, and iodo.

For compounds of formula III, preferred R⁷ and R⁸ (R^(2a)) substituentsare methyl, isopropyl, benzyl, and methoxymethyl. Compounds in which R⁷and R⁸ each are methyl are prepared via the procedure described in theabove-referenced Jones patent. Another preferred hydroxy protectinggroup is methoxymethyl. However, a formula IV compound, as shown below,is first prepared bearing the preferred methyl or other hydroxyprotecting group(s). These protecting groups are then removed, formingphenolic moieties, which are then reprotected with methoxymethylprotecting groups.

Compounds of formula III are also prepared in which R⁷ hydroxyprotecting groups are selectively removed, leaving the R⁸ (R^(2a))hydroxy protecting group as part of the final product. The same is truein which the R⁸ (R^(2a)) hydroxy protecting group is selectivelyremoved, leaving the R⁷ hydroxy protecting group in place. For example,R⁷ is isopropyl or benzyl and R⁸ (R^(2a)) is methyl. The isopropyl orbenzyl moiety is selectively removed via standard procedures, and the R⁸methyl protecting group is left as part of the final product.

The first steps of the present process for preparing certain compoundsof formula I include selectively placing a leaving group at the 3position of a formula III compound, coupling the reaction product of thefirst step with a 4-(protected-hydroxy)phenol, and removing the phenol'shydroxy protecting group. The present process is depicted in Scheme Ibelow. ##STR12##

In the first step of Scheme I, an appropriate leaving group isselectively placed at the 3-position of the formula III startingmaterial via standard procedures. Appropriate R⁹ leaving groups includethe sulfonates such as methanesulfonate, 4-bromobenzenesulfonate,toluenesulfonate, ethanesulfonate, isopropanesulfonate,4-methoxybenzenesulfonate, 4-nitrobenzenesulfonate,2-chlorobenzenesulfonate, triflate, and the like, halogens such asbromo, chloro, and iodo, and other related leaving groups. However, toinsure proper placement of the leaving group, the named halogens arepreferred, and bromo is especially preferred.

The present reaction is carried out using standard procedures. Forexample, when the preferred halogenating agents are used, an equivalentof such a halogenating agent, preferably bromine, is reacted with anequivalent of the formula III substrate, in the presence of a suitablesolvent reaction is run at a temperature from about 40° C. to about 80°C.

The reaction product from the above process step, a compound of formulaIV, is then reacted with a 4-(protected-hydroxy)phenol to form compoundsof formula IIa in which R⁶ is a selectively removable hydroxy protectinggroup. Generally, the 4-hydroxy protecting moiety of the phenol may beany known protecting group which can be selectively removed withoutremoving, in this instance, the R⁷ and, when present, R⁸ moieties of aformula IIa compound. Preferred R⁶ protecting groups includemethoxymethyl, when R⁷ and/or R⁸ are not methoxymethyl, and benzyl. Ofthese, benzyl is especially preferred. The 4-(protected-hydroxy)phenolreactants are commercially available or can be prepared via standardprocedures.

This coupling reaction is known in the art as an Ullman reaction and isrun according to standard procedures [see e.g., Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, Fourth Edition, 3-16,(J. March, ed., John Wiley & Sons, Inc. 1992); Jones, C. D., J. Chem.Soc. Perk. Trans. I, 4:407 (1992)].

In general, equivalent amounts of the two aryl substrates, in thepresence of up to an equimolar amount of a copper(I) oxide catalyst andan appropriate solvent, are heated to reflux under an inert atmosphere.Preferably, an equivalent of a formula IV compound in which R⁹ is bromois reacted with an equivalent amount of 4-benzyloxyphenol in thepresence of an equivalent of cuprous oxide.

Appropriate solvents for this reaction are those solvents or mixture ofsolvents which remain inert throughout the reaction. Typically, organicbases, particularly a hindered base such as, for example,2,4,6-collidine, are preferred solvents.

The temperature employed in this step should be sufficient to effectcompletion of this coupling reaction, and will influence the amount oftime required therefore. When the reaction mixture is heated to refluxunder an inert atmosphere such as nitrogen, the time-to-completionusually will be from about 20 to about 60 hours.

Following coupling, which forms a formula IIa compound, formula IIbcompounds are prepared by selectively removing the R⁶ hydroxy protectinggroup of a formula IIa compound via well known reduction procedures. Itis imperative that the selected procedure will not affect the R⁷ and,when present, R⁸ hydroxy protecting groups.

When R⁶ is the preferred benzyl moiety, and R⁷ and, when present, R⁸each are methyl, the present process step is carried out via standardhydrogenolysis procedures. Typically, the formula IIa substrate is addedto a suitable solvent or mixture of solvents, followed by the additionof a proton donor to accelerate the reaction and an appropriatehydrogenation catalyst.

Appropriate catalysts include noble metals and oxides such as palladium,platinum, and rhodium oxide on a support such as carbon or calciumcarbonate. Of these, palladium-on-carbon, particularly 10%palladium-on-carbon, is preferred.

Solvents for this reaction are those solvents or mixture of solventswhich remain inert throughout the reaction. Typically, ethylacetate andC₁ -C₄ aliphatic alcohols, particularly ethanol, is preferred.

For the present reaction, hydrochloric acid serves as an adequate andpreferred proton donor.

When run at ambient temperature and a pressure ranging form about 30 psito about 50 psi, the present reaction runs quite rapidly. Progress ofthis reaction may be monitored by standard chromatographic techniquessuch as thin layer chromatography.

Compounds of formula IIa and IIb are novel, are encompassed within thegenus described herein as formula II compounds, and are useful forpreparing the pharmaceutically active compounds of formula I.

Upon preparation of a formula IIb compound, it is reacted with acompound of formula V ##STR13## wherein R³ and n are as defined above,and Q is a bromo or, preferably, a chloro moiety, to form a compound offormula VI. The formula VI compound is then deprotected to form acompound of formula Ia. These steps of the present process are shown inScheme II below ##STR14## wherein R³, R⁷, R^(2a), and n are as definedabove, and R^(2b) is --H, --OH, or halo.

In the first step of the process shown in Scheme II, the alkylation iscarried out via standard procedures. Compounds of formula V arecommercially available or are prepared by means well known to one ofordinary skill in the art. Preferably, the hydrochloride salt of aformula V compound, particularly 2-chloroethylpiperidine hydrochloride,is used.

Generally, at least about 1 equivalent of formula IIb substrate arereacted with 2 equivalents of a formula V compound in the presence of atleast about 4 equivalents of an alkali metal carbonate, preferablycesium carbonate, and an appropriate solvent.

Solvents for this reaction are those solvents or mixture of solventswhich remain inert throughout the reaction. N,N-dimethylformamide,especially the anhydrous form thereof, is preferred.

The temperature employed in this step should be sufficient to effectcompletion of this alkylation reaction. Typically, ambient temperatureis sufficient and preferred.

The present reaction preferably is run under an inert atmosphere,particularly nitrogen.

Under the preferred reaction conditions, this reaction will run tocompletion in about 16 to about 20 hours. Of course, the progress of thereaction can be monitored via standard chromatographic techniques.

As an alternative for preparing compounds of formula VI, a formula IIbcompound is reacted with an excess of an alkylating agent of the formula

    Q--(CH.sub.2).sub.n --Q'

wherein Q and Q' each are the same or different leaving group, in analkali solution. Appropriate leaving groups are the aforementionedleaving groups used in the preparation of compounds of formula IV.

A preferred alkali solution for this alkylation reaction containspotassium carbonate in an inert solvent such as, for example, methyethylketone (MEK) or DMF. In this solution, the 4-hydroxy group of thebenzoyl moiety of a formula IIb compound exists as a phenoxide ion whichdisplaces one of the leaving groups of the alkylating agent.

This reaction is best when the alkali solution containing the reactantsand reagents is brought to reflux and allowed to run to completion. Whenusing MEK as the preferred solvent, reaction times run from about 6hours to about 20 hours.

The reaction product from this step is then reacted with 1-piperidine,1-pyrrolidine, methyl-1-pyrrolidine, dimethyl-1-pyrrolidine,4-morpholine, dimethylamine, diethylamine, diisopropylamine, or1-hexamethyleneimine, via standard techniques, to form compounds offormula VI. Preferably, the hydrochloride salt of piperidine is reactedwith the alkylated compound of formula IIb in an inert solvent, such asanhydrous DMF, and heated to a temperature in the range from about 60°C. to about 110° C. When the mixture is heated to a preferredtemperature of about 90° C., the reaction only takes about 30 minutes toabout 1 hour. However, changes in the reaction conditions will influencethe amount of time this reaction needs to be run for completion. Ofcourse, the progress of this reaction step can be monitored via standardchromatographic techniques.

Compounds of formula VI, in which R⁷ and when present, R⁸ each are C₁-C₄ alkyl, preferably methyl, and in which R^(2a) is --H or halo, arenovel and are pharmaceutically active for the methods herein described.Accordingly, such compounds are encompassed by the definition herein ofcompounds of formula I.

Certain preferred compounds of formula I are obtained by cleaving the R⁷and, when present, R⁸ hydroxy protecting groups of formula VI compoundsvia well known procedures. Numerous reactions for the formation andremoval of such protecting groups are described in a number of standardworks including, for example, Protective Groups in Organic Chemistry,Plenum Press (London and New York, 1973); Green, T. W., ProtectiveGroups in Organic Synthesis, Wiley, (New York, 1981); and The Peptides,Vol. I, Schrooder and Lubke, Academic Press (London and New York, 1965).Methods for removing preferred R⁷ and/or R⁸ hydroxy protecting groups,particularly methyl and methoxymethyl, are essentially as described inthe Examples, infra.

Compounds of formula Ia are novel, are pharmaceutically active for themethods herein described, and are encompassed by formula I as definedherein.

Compounds of formula I in which R¹ is --H are prepared via the syntheticroute shown below in Scheme III. Using this route, a 3-position leavinggroup (R⁹) is placed on commercially available thianaphthene (formulaVII) to form a compound of formula VIII, which is then coupled with a4-(protected-hydroxy)phenol, providing compounds of formula IX.##STR15## wherein R⁶ is a hydroxy protecting group which can beselectively removed and R⁹ is a leaving group.

The compound of formula VII is commercially available. Preparation offormulae VIII and IX compounds, including the definition of R⁶ and R⁹substituents, as well as preferred reactants and conditions, unlessotherwise herein stated, are the same as described above and shown inScheme I, supra.

Compounds of formula IX are then arylated via Suzuki coupling [see,e.g., Suzuki, A., Pure and Appl. Chem., 6(2):213-222 (1994)]. Using oneSuzuki coupling option, a formula IX compound is selectively halogenatedat the 2-position, and then coupled with an arylboronic acid compound offormula XIa (Route A of Scheme IV below).

Preferably, however, an arylboronic acid of formula Xb is formed from acompound of formula IX, and then reacted with a halo-arene of formulaXIb to give novel intermediates of formula IIc (Route B of Scheme IVbelow). Such novel intermediates are useful for preparingpharmaceutically active compounds of the present invention (formula Ibcompounds) via alkylation and deprotection. ##STR16## wherein R^(2a),R^(2b), R³, R⁶ and n are as defined above;

X is iodo, bromo, or fluoro, in the order of preference; and

X' is iodo, bromo, or fluoro, in the order of preference, or triflate.

The first step in Route A in Scheme IV is the 2-position iodination orbromination of a formula IX compound using standard procedures.Generally, a formula IX compound is reacted with a slight excess ofn-butyllithium in hexane, in an appropriate solvent and under an inertatmosphere such as nitrogen, followed by the dropwise addition of aslight excess of the desired halogenating agent in an appropriatesolvent. Preferably, the halogenating agent for this step is iodine, butthe use of bromine, N-bromosuccinimide is also permitted.

Appropriate solvents include an inert solvent or mixture of solventssuch as, for example, diethyl ether, dioxane, and tetrahydrofuran (THF).Of these, tetrahydrofuran, particularly anhydrous THF, is preferred.

The present selective, 2-position halogenation reaction optionally isrun at a temperature from about -75° C. to about 85° C.

The product of the above reaction, a halo-arene of formula Xa, is thencoupled with an arylboronic acid of formula XIa, via standard Suzukicoupling procedures, to provide compounds of formula IIc. Compounds offormula XIa, in which R^(2a) is --H, halo, or --OR⁸ (R⁸ is a hydroxyprotecting group as defined, supra) are derived from commerciallyavailable compounds via procedures well known to one of ordinary skillin the art (see, e.g., March J.; and Suzuki, A., supra).

In the present coupling reaction, a slight excess of a formula XIacompound is reacted with each equivalent of a formula Xa compound in thepresence of a palladium catalyst and an appropriate base in an inertsolvent such as toluene.

Although various palladium catalysts drive Suzuki coupling reactions,the catalyst selected usually is reaction specific. Thus, the use oftetrakistriphenylphosphine palladium in the present reaction is highlypreferred.

Likewise, various bases may be used in the present coupling reaction.However, it is preferred to use an alkali metal carbonate, particularly2N sodium carbonate.

The temperature employed in this step should be sufficient to effectcompletion of the coupling reaction. Typically, heating the reactionmixture to reflux for a period from about 2 to about 4 hours is adequateand preferred.

In Route B of Scheme IV, a 2-position arylboronic of formula Xb isprepared using well known procedures. Generally, a compound of formulaIX is treated with a slight excess of n-butyllithium in hexanes, in anappropriate solvent and under an inert atmosphere such as nitrogen,following by the dropwise addition of an appropriate trialkylborate.

Appropriate solvents include an inert solvent or mixture of solventssuch as, for example, diethyl ether, dioxane, and tetrahydrofuran (THF).THF, particularly anhydrous THF, is preferred.

The preferred trialkylborate used in the present reaction istriisopropyl borate.

The product of this reaction, a compound of formula Xb, is then reactedwith a aryl halide or aryl triflate of formula XIb, via standard Suzukicoupling procedures, to provide compounds of formula IIc. The preferredreaction conditions for the present reaction are as described for thereaction of compounds of formulae XIa and Xa, in Scheme IV, which alsoprovide compounds of formula IIc.

The transformation of compounds of formula IIc to formula Ia compoundsis carried out as described above for the conversion of formula IIacompounds to compounds of formula Ia.

Compounds of formulae IIc and IId are novel, and are useful for thepreparation of pharmaceutically active compounds of the presentinvention.

Compounds of formulae XII and Ib also are novel, are useful for themethods herein described, and are encompassed by formula I as hereindefined.

Compounds of formula I in which either R¹ or R² is --H and the other R¹or R² substituent is --OH also are prepared from compounds of formula Iin which both R¹ or R² are --OH. The dihydroxy compound of formula I isconverted to a mixture of 6- and 4-monotriflates, and the triflatemoiety is reduced to hydrogen [see, Saa, J. M., et al., J. Org. Chem.,55:991 (1990)]. The resulting mixture of monohydroxy derivatives, eitheras the free base or pharmaceutically acceptable salt, preferably thehydrochloride salt, can then be separated by standard crystallizationtechniques.

In general, a dihydroxy compound of formula I is treated with about 4 toabout 6 equivalents of a amine base, such as triethylamine, in anon-reactive solvent followed by the addition of 1 equivalent oftrifluoromethanesulfonic anhydride. A statistical mixture of mono- anddi-triflates are produced and separated by standard chromatographictechniques. A preferred solvent for this step is anhydrousdichloromethane.

When run at a temperature range from about 0° C. to about 25° C., thepresent reaction is completed within from about 1 to about 5 hours.

The isolated mixture of mono-triflated compounds is then hydrogenated,in a non-reactive solvent, in the presence of from about 3 to about 6equivalents of an amine base, preferably triethylamine, and ahydrogenation catalyst such as palladium-on-carbon, which is preferred.Preferred solvents for this reaction include ethyl acetate and ethanolor, alternatively, a mixture thereof. When this step of the presentreaction is run under about 40 psi of hydrogen gas, at ambienttemperature, the reaction time is from about 2 hours to about 5 hours.

The resulting mixture of monohydroxy derivatives of formula I havedifferent solubilities in ethyl aceate and the 6-hydroxy-4'-hydrogenderivatives can be partially separated from the 6-hydrogen-4'-hydroxyderivatives by selective crystallization. Further separation, whichprovides pure monohydroxy compounds of formula I, can be achieved byconversion of the enriched mixtures to the hydrochloride salts followedby crystallization from ethyl acetate-ethanol.

A more direct method for the preparation of compounds of formula I inwhich either R¹ or R² is --H and the other R¹ or R² substituent is --OH,as well as an alternative method for the preparation of compounds offormula I in which either R¹ or R² is --H and the other R¹ or R²substituent is --O--(C₁ -C₄ alkyl) uses a compound of the formula##STR17## wherein R³ and n are defined above;

R^(1c) is --OH or --O--(C₁ -C₄ alkyl); and

R^(2c) is --OH or --O--(C₁ -C₄ alkyl);

providing when R^(1c) is --OH, R^(2c) is --O--(C₁ -C₄ alkyl), and whenR^(1c) is --O--(C₁ -C₄ alkyl) R^(2c) is --OH.

In this process, the hydroxy moiety of such a compound is converted to atriflate derivative by treatment with trifluoromethane sulfonicanhydride. The triflate moiety is then reduced under standardconditions, preferably by catalytic hydrogenation. The hydroxyprotecting moiety is then removed via standard procedures, as in thoseherein described, providing compounds of formula I in which either R¹ orR² is --H and the other R¹ or R² substituent is --OH.

Another alternative, and preferred, method for the preparation ofcompounds of the present invention is shown in Scheme V. In the presentprocess, the sulfur atom of a formula IV compound (infra) is oxidized toform a sulfoxide (formula XIV), which is then reacted with anucleophilic group to introduce the oxygen or sulphur atom linker offormula I and formula II compounds. The sulfoxide moiety of formula XVIcompounds is then reduced to provide certain compounds of the presentinvention. ##STR18## wherein each variable has its previously definedmeaning.

In the first step of this process, a compound of formula IV isselectively oxidized to the sulfoxide. A number of known methods areavailable for the process step [see, e.g., Madesclaire, M., Tetrahedron,42 (20); 5459-5495 (1986); Trost, B. M., et al., Tetrahedron Letters, 22(14); 1287-1290 (1981); Drabowicz, J., et al., Synthetic Communications,11 (12); 1025-1030 (1981); Kramer, J. B., et al., 34th National OrganicSymposium, Williamsburg, Va., Jun. 11-15, 1995]. However, many oxidantsprovide only poor conversion to the desired product as well assignificant over-oxidation to the sulfone. The present, novel process,however, converts a formula IV compound to a sulfoxide of formula XIV inhigh yield with little or no formation of sulfones. This processinvolves the reaction of a formula IV compound with about 1 to about 1.5equivalents of hydrogen peroxide in a mixture of about 20% to about 50%trifluoroacetic acid in methylene chloride. The reaction is run at atemperature from about 10° C. to about 50° C., and usually required fromabout 1 to about 2 hours to run to completion.

Next, the 3-position leaving group (R⁹) is displaced by the desirednucleophilic derivative of formula XV. Such nucleophilic derivatives areprepared via standard methods.

In this step of the process, the acidic proton of the nucleophilic groupis removed by treatment with a base, preferably a slight excess ofsodium hydride or potassium tertbutoxide, in a polar aprotic solvent,preferably DMF or tetrahydrofuran. Other bases that can be employedinclude potassium carbonate and cesium carbonate. Additionally, othersolvents such as dioxane or dimethylsulfoxide can be employed. Thedeprotonation is usually run at a temperature between about 0° C. andabout 30° C., and usually requires about 30 minutes for completion. Acompound of formula XIV is then added to the solution of thenucleophile. The displacement reaction is run at a temperature between0° C. and about 50° C., and is usually run in about 1 to about 2 hours.The product is isolated by standard procedures.

When a benzyl moiety is used as a hydroxy protecting group,hydrogenolysis of the sulfoxide moiety will also provide removal of thebenzyl protecting group, eliminating the requirement for selectivelyremoving such a group at a later stage in the process.

In the next step of the present process, novel sulfoxides of formulaeXVI a, b, c, and d (collectively formula XVI) are reduced to abenzothiophene compound of formulae IIg, Ic, IIe, and Id, respectively.Prior to the present reduction process, compounds of formulae IIg andIIe can first be alkylated as herein described. Reduction of thesulfoxide compounds can be accomplished by using one of a multitude ofmethods known in the art including, for example, hydride reduction(lithium aluminum hydride), catalytic hydrogenation, transferhydrogenolysis and trimethylsilyl iodide (TMS-I). In this reduction, thechoice of reagent is dependent upon the compatibility of otherfunctionalities in the molecule. For the compounds described in thepresent invention, lithium aluminum hydride (LiAlH₄) and transferhydrogenolysis (palladium black/ammonium formate) are the preferredreagents. For LiAlH₄ reduction, appropriate solvents such as, forexample, diethyl ether, dioxane, and tetrahydrofuran (THF). Of these,THF, particularly anhydrous THF, is preferred. For transferhydrogenolysis, alcohol solvents, particularly ethanol, is preferred.The reaction is run at a temperature from about 0° C. to about 60° C.,and requires from about 0.5 hours to about 2 hours for completion.

When desired, the hydroxy protecting group or groups of the products ofthe process shown in Scheme V can be removed, and a salt of the productof any step of the process. Accordingly, the present invention providesa process for preparing compounds of the formula ##STR19## whereinR^(1a) is --H or --OR^(7a) in which R^(7a) is --H or a hydroxyprotecting group;

R^(2a) is --H, halo, or --OR^(8a) in which R^(8a) is --H or a hydroxyprotecting group;

R³ is 1-piperidinyl, 1-pyrrolidino, methyl-1-pyrrolidinyl,dimethyl-1-pyrrolidino, 4-morpholino, dimethylamino, diethylamino,diisopropylamino, or 1-hexamethyleneimino;

n is 2 or 3; and

Z is --O-- or --S--;

or a pharmaceutically acceptable salt thereof, comprising

a) oxidizing the sulfur atom of a formula IV compound ##STR20## whereinR^(1a) and R^(2a) are as previously defined; and

R⁹ is a leaving group;

b) reacting the product of step a), a compound of formula XIV ##STR21##with a nucleophilic group of the formula ##STR22## wherein R¹² is --OHor --SH; c) reducing the product of step b), a compound of formula XVI##STR23## to provide a compound of the formula ##STR24## d) optionallyremoving the R^(1a) and/or R^(2a) hydroxy protecting groups, whenpresent, of the product of step c); and

e) optionally forming a salt of the product of step c) or step d).

This novel process also provides novel compounds of formulae XIV, andXVI a, b, c, and d, each of which is an intermediate useful forpreparing the pharmaceutically active compounds of the presentinvention.

Compounds of formulae I in which Z is S are also prepared using theprocess described below in Scheme VI in which a compound of formula IVais metallated. The resulting product, a compound of formula XVII isreacted with a 4-(protected hydroxy)phenyl disulfide of formula XVIII,and the phenol protecting group of a formula IIe compound is removed toprovide compounds of formula IIf. One will note that, in using thisprocess, R² cannot be halo because of chemical limitations. ##STR25##wherein R^(1a) is --H or --OR⁷ and R⁷ is a hydroxy protecting group;

R^(2a) is --H, or --OR⁸ and R⁸ is a hydroxy protecting group;

R⁶ is a hydroxy protecting group which can be selectively removed;

R⁹ is a leaving group; and

M is a metal ion.

In the first two steps of Scheme VI, a formula IVa compound ismetallated via well known procedures. Most commonly, and preferably, aformula IVa compound is treated with a slight excess of n-butyllithiumin hexanes in an appropriate solvent, followed by the dropwise additionof a solution of a disulfide compound of formula XVIII in an appropriatesolvent.

Both of these reaction steps are run under an inert atmosphere such asnitrogen, while appropriate solvents for both steps include one or moreinert solvents such as diethyl ether, dioxane, and THF. Of these, THF,particularly the anhydrous form thereof, is preferred. In addition, thepresent reaction steps are run at a temperature from about -78° C. toabout 85° C.

In the first step of the present reaction, a metallated compound offormula XVII is provided. The 4-(protected-hydroxy)phenyl disulfide (aformula XVIII compound) which is reacted with such a formula XVIIcompound to give a compound of formula IIe, is prepared by protectingthe hydroxy group of commercially available 4-hydroxyphenylsulfide withan appropriate protecting group via procedures known in the art. Apreferred R⁶ protecting group is methoxymethyl, providing R⁷ and R⁸, ifeither or both are present, is a hydroxy protecting group other thanmethoxymethyl. It is imperative that the R⁶ hydroxy protecting group isa moiety different than those formed by R⁷ and R⁸ hydroxy protectinggroups, when present, so that the R⁶ group can selectively be removed,via standard procedures, to provide compounds of formula IIf.

To effect deprotection by removal of the R⁶ protecting group, a formulaIIe compound in a protic solvent or mixture of solvents is reacted in anacid media containing at least one equivalent of acid, preferablymethanesulfonic acid, and heating from about 25° to about 110° C.Typically, the reaction time is from about 6 to about 24 hours, but theprogress of the reaction may be monitored via standard chromatographictechniques.

Appropriate solvents for the present reaction include, for example,water and methanol.

Compounds of formulae IIe and IIf are novel, are useful for preparingpharmaceutically active compounds of formula I and are hereinencompassed within the above depiction of formula II.

Compounds of formula Id ##STR26## wherein R^(1b) is --H or --OH;

R^(2b) is --H or --OH; and

R³ and n, are as defined above, are prepared by using theabove-described procedures related to the process steps shown in SchemesII and IV. Such compounds of formula Id also are novel, are useful forthe methods of the present invention, and are herein encompassed withinthe above depiction of formula I.

Compounds of formula I, in which R¹ and R² are different hydroxyprotecting groups or either R¹ and R² is a hydroxy protecting group andthe other is hydroxy are selectively prepared by using a modified2-arylbenzothiophene starting material of formula III above, providingthat hydroxy protecting groups designated R⁷ and R⁸ are sufficientlydifferent so that one protecting group is removed while the other groupremains. Such 2-arylbenzothiophenes are prepared via procedures wellknown in the art.

Particularly useful for the preparation of formula I compounds in whichR¹ and R² are different protecting groups is Suzuki coupling asdescribed above in Scheme IV. However, 6-(protected hydroxy)benzothiophene-2-boronic acid is reacted with a formula XIb compoundabove in which R^(2a) is --OR⁸ and R⁷ does not equal R⁸. This reactionallows preparation of compounds of the present invention in which R⁷ andR⁸ are different hydroxy protecting groups so that one protecting groupmay selectively be removed and the other remains as a moiety of thefinal product. Preferably, the R⁷ protecting group, especially benzyl orisopropyl, is removed to form a hydroxy moiety while the R⁸ protectinggroup, particularly methyl, remains.

Suzuki coupling also is accomplished by using the above-describedprocedures but replacing a formula XIb compound with a compound offormula XIX ##STR27## wherein R^(8a) is C₁ -C₆ alkyl sulfonate,preferably methansulfonate or C₄ -C₆ aryl sulfonate; and

R¹⁰ is a leaving group, preferably bromo or triflate.

In this process, a 6-(protecting hydroxy) benzothiophene-2-boronic acidas described above is reacted with a compound of formula XIX to providea compound of formula XX, which is reacted with boron tribromide inmethylene chloride to provide a monohydroxy compound which issubsequently converted to, for example, a benzyl moiety by standardprocedures (formula XXI). The 4'-sulfonate ester is then selectivelyremoved by basic hydrolysis or, preferably, by treatment with LiAlH₄, inan appropriate aprotic solvent such as, for example, THF. This reactionprovides a compound of formula XXII which is finally, for example,methylated at the 4'-position via standard procedures (formula IIIa). Ofcourse, one skilled in the art will recognize that various processes canbe utilized to provide formula IIIa compounds in which the hydroxyprotecting groups are other than shown in Scheme VII below, but whichcan be selectively removed to provide monohydroxy compounds of formula Iof the present invention. ##STR28## Compounds of IIIa are then subjectedto the various processes herein described to provide compounds offormula I and II of the present invention.

Other preferred compounds of formula I are prepared by replacing 6-and/or 4'-position hydroxy moieties, when present, with a moiety of theformula --O--CO--(C₁ -C₆ alkyl), or --O--SO₂ --(C₂ -C₆ alkyl) via wellknown procedures. See, e.g., U.S. Pat. No. 4,358,593.

For example, when an --O--CO(C₁ -C₆ alkyl) group is desired, a mono- ordihydroxy compound of formula I is reacted with an agent such as acylchloride, bromide, cyanide, or azide, or with an appropriate anhydrideor mixed anhydride. The reactions are conveniently carried out in abasic solvent such as pyridine, lutidine, quinoline or isoquinoline, orin a tertiary amine solvent such as triethylamine, tributylamine,methylpiperidine, and the like. The reaction also may be carried out inan inert solvent such as ethyl acetate, dimethylformamide,dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone,methyl ethyl ketone, and the like, to which at least one equivalent ofan acid scavenger (except as noted below), such as a tertiary amine, hasbeen added. If desired, acylation catalysts such as4-dimethylaminopyridine or 4-pyrrolidinopyridine may be used. See, e.g.,Haslam, et al., Tetrahedron, 36:2409-2433 (1980).

The present reactions are carried out at moderate temperatures, in therange from about -25° C. to about 100° C., frequently under an inertatmosphere such as nitrogen gas. However, ambient temperature is usuallyadequate for the reaction to run.

Acylation of a 6-position and/or 4'-position hydroxy group also may beperformed by acid-catalyzed reactions of the appropriate carboxylicacids in inert organic solvents. Acid catalysts such as sulfuric acid,polyphosphoric acid, methanesulfonic acid, and the like are used.

The aforementioned R¹ and/or R² groups of formula I compounds also maybe provided by forming an active ester of the appropriate acid, such asthe esters formed by such known reagents such asdicyclohexylcarbodiimide, acylimidazoles, nitrophenols,pentachlorophenol, N-hydroxysuccinimide, and 1-hydroxybenzotriazole.See, e.g., Bull. Chem. Soc. Japan, 38:1979 (1965), and Chem. Ber., 788and 2024 (1970).

Each of the above techniques which provide --O--CO--(C₁ -C₆ alkyl)moieties are carried out in solvents as discussed above. Thosetechniques which do not produce an acid product in the course of thereaction, of course, do not call for the use of an acid scavenger in thereaction mixture.

When a formula I compound is desired in which the 6- and/or 4'-positionhydroxy group of a formula I compound is converted to a group of theformula --O--SO₂ --(C₂ -C₆ alkyl), the mono- or dihydroxy compound isreacted with, for example, a sulfonic anhydride or a derivative of theappropriate sulfonic acid such as a sulfonyl chloride, bromide, orsulfonyl ammonium salt, as taught by King and Monoir, J. Am. Chem. Soc.,97:2566-2567 (1975). The dihydroxy compound also can be reacted with theappropriate sulfonic anhydride or mixed sulfonic anhydrides. Suchreactions are carried out under conditions such as were explained abovein the discussion of reaction with acid halides and the like.

Although the free-base form of formula I compounds can be used in themethods of the present invention, it is preferred to prepare and use apharmaceutically acceptable salt form. Thus, the compounds used in themethods of this invention primarily form pharmaceutically acceptableacid addition salts with a wide variety of organic and inorganic acids,and include the physiologically acceptable salts which are often used inpharmaceutical chemistry. Such salts are also part of this invention.Typical inorganic acids used to form such salts include hydrochloric,hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric,and the like. Salts derived from organic acids, such as aliphatic monoand dicarboxylic acids, phenyl substituted alkanoic acids,hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphaticand aromatic sulfonic acids, may also be used. Such pharmaceuticallyacceptable salts thus include acetate, phenylacetate, trifluoroacetate,acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate,naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate,b-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate,caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate,heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate,malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate,oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate,propionate, phenylpropionate, salicylate, sebacate, succinate, suberate,sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate,benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate,ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate,xylenesulfonate, tartarate, and the like. Preferred salts are thehydrochloride and oxalate salts.

The pharmaceutically acceptable acid addition salts are typically formedby reacting a compound of formula I with an equimolar or excess amountof acid. The reactants are generally combined in a mutual solvent suchas diethyl ether or ethyl acetate. The salt normally precipitates out ofsolution within about one hour to 10 days and can be isolated byfiltration or the solvent can be stripped off by conventional means.

The pharmaceutically acceptable salts generally have enhanced solubilitycharacteristics compared to the compound from which they are derived,and thus are often more amenable to formulation as liquids or emulsions.

Representative preferred compounds of the present invention include thefollowing:

Group I:

[6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide)

[6-isopropoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide)

[6-methoxy-2-(4-isopropoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide)

[2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide)

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)

[3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)

[6-benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide)

[6-isopropoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide)

[6-methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide)

[6-methoxy-2-(4-isopropoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide)

[6-benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)

[6-isopropoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene-(S-oxide)

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene-(S-oxide)

[6-methoxy-2-(4-methoxyphenyl)-3-(4-methoxymethyleneoxy)thiophenoxy]benzo[b]thiophene

[6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)thiophenoxy]benzo[b]thiophene

Group II:

[3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[3-[4-[2-(1-pyrolidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[3-[4-[2-(1-N,N-diethylamino)ethoxylphenoxy]-2-(4-hyhydroxyphenyl)]benzo[b]thiophene

3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(phenyl)]benzo [b]thiophenehydrochloride

[3-[4-[2-(1-piperidinyl)ethoxylphenoxy]-2-(4-fluorophenyl)]benzo[b]thiophene

[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene

[6-isopropoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene

[6-methoxy-2-(4-isopropoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-pyrolodinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(morpholino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-(4-[3-(piperidino)propoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[3-(1-N,N-diethylamino)propoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiopheneoxalate

[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-pyrolidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(morpholino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[3-(1-N,N-diethylamino)propoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-N,N-diisopropylamino)-ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[3-(piperidino)propoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-benzyloxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-benzyloxy-3-[4-[2-(1-hexamethylimino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-benzyloxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-benzyloxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-isopropoxyoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-isopropoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-isopropoxy-3-[4-[2-(1-hexamethylimino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-isopropoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-isopropoxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-hexamethylimino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-hexamethylimino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-hydrooxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-methoxy-3-(4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-hydrooxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-(2-(1-morpholino)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-benzoyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-benzoyloxyphenyl)]benzo[b]thiophenehydrochloride

[6-ethylsulfonyloxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-ethylsulfonyloxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-ethylsulfonyloxyphenyl)]benzo[b]thiophenehydrochloride

[6-ethylsulfonyloxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-triflouromethanesulfonyloxyphenyl)]benzo[b]thiophene

3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-benzoyloxyphenyl)]benzo[b]thiophenehydrochloride

3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-pivaloyloxyphenyl)]benzo[b]thiophenehydrochloride

3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-butylsulfonyloxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-benzyloxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-benzyloxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-benzyloxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-benzyloxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-isopropoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-isopropoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-isopropoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-isopropoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-isopropoxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene

[6-methoxy-3-(4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene

6[-methoxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-isopropoxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene

[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

[6-hydroxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride

6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-phenyl]benzo[b]thiophenehydrochloride

The following examples are presented to further illustrate thepreparation of compounds of the present invention. It is not intendedthat the invention be limited in scope by reason of any of the followingexamples.

NMR data for the following Examples were generated on a GE 300 MHz NMRinstrument, and anhydrous d-6 DMSO was used as the solvent unlessotherwise indicated.

Preparation 1

Preparation of[3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene[3-(4-benzyloxy)phenoxy]benzo[b]thiophene ##STR29##

To a solution of 3-bromo-benzo[b]thiophene (69.62 g, 0.325 mol) in 55 mLof anhydrous collidine under N₂ was added 4-benzyloxyphenol (97.6 g,0.488 mol) and cuprous oxide (23.3 g, 0.163 mol). The mixture was heatedto reflux for 24 hours. Upon cooling, the reaction mixture was dilutedwith ethyl acetate (200 mL) and the crude mixture filtered through a padof Celite® (Aldrich, Milwaukee, Wis.) to remove inorganic salts. Thefiltrate was washed with 1N hydrochloric acid (3×150 mL). The organicwas dried (sodium sulfate) and concentrated in vacuo to a liquid.Thianaphthene was removed by distillation (10 mm Hg, 115-120° C.). Theremainder of the material was chromatographed (silicon dioxide, hexanes:ethyl acetate 85:15) to provide 12.2 g of benzo[b]thiophene and 12.95 g(35% based on recovered starting material) of[3-(4-benzyloxy)phenoxy]benzo-[b]thiophene as an off-white solid. mp84-86° C. ¹ H NMR (CDCl₃) _(d) 7.91-7.83 (m, 2H), 7.47-7.34 (m, 7H),7.04 (q, J_(AB) =9.0 Hz, 4H), 6.47 (s, 1H), 5.07 (s, 2H). Anal. Calcd.for C₂₁ H₁₆ O₂ S: C, 75.88; H, 4.85. Found: C, 75.75; H, 5.00.

Preparation 2 ##STR30##

To a solution of [3-(4-benzyloxy)phenoxy]benzo[b]thiophene (6.00 g, 18.1mmol) in anhydrous tetrahydrofuran (100 mL) under N₂ at -78° C. wasadded n-butyllithium (12.4 mL, 19.9 mmol, 1.6 M in hexanes) dropwise viasyringe. The solution turned from colorless to deep orange. Afterstirring for 20 minutes at -78° C., the lithio species was treated withI₂ (5.03, 19.9 mmol), added dropwise via cannula as a solution in 50 mLof anhydrous tetrahydrofuran. Upon completion of the addition, thereaction turned light yellow in color, and was allowed to slowly warm toroom temperature. The reaction was quenched by the addition of 0.1 Nsodium sulfite solution (200 mL). The layers were separated and theaqueous extracted with ethyl acetate (2×150 mL). The organic wascombined, dried (sodium sulfate), and concentrated in vacuo to give anoil that crystallized on standing. Recrystallization from hexanes/ethylether yielded 7.10 g (86%) of[2-Iodo-3-(4-benzyloxy)phenoxy]benzo[b]thiophene as a white crystallinepowder. mp 87-92° C. ¹ H NMR (CDCl₃) _(d) 7.72 (d, J=8.1 Hz, 1H),7.47-7.20 (m, 8H), 6.89 (s, 4H), 5.01 (s, 2H). Anal. Calcd. for C₂₁ H₁₅O₂ SI: C, 55.03; H, 3.30. Found: C, 55.29; H, 3.31.

Preparation 3 ##STR31##

To a solution of [2-Iodo-3-(4-benzyloxy)phenoxy]benzo[b]thiophene (4.50g, 9.82 mmol) in toluene (20 mL) was added 4-(tertbutoxy)phenyl boronicacid (2.28 g, 11.75 mmol) followed bytetrakistriphenylphosphinepalladium (0.76 g, 0.66 mmol). To thissolution was added 14.5 mL of 2N sodium carbonate solution. Theresulting mixture was heated to reflux for 3 hours. Upon cooling, thereaction was diluted with 150 mL of ethyl acetate. The organic waswashed with 0.1N sodium hydroxide (2×100 mL) and then dried (sodiumsulfate). Concentration produced a semi-solid that was dissolved inchloroform and passed through a pad of silicon dioxide. Concentrationproduced an oil that was triturated from hexanes to yield 4.00 g (91%)of [2-(4-tertbutyloxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene asa white powder. mp 105-108° C. ¹ H NMR (CDCl₃) _(d) 7.77 (d, J=7.7 Hz,1H), 7.68 (d, J=8.6 Hz, 2H), 7.43-7.24 (m, 8H), 6.98 (d, J=8.6 Hz, 2H),6.89 (q, J_(AB) =9.3 Hz, 4H), 4.99 (s, 2H), 1.36 (s, 9H). FD mass spec:480. Anal. Calcd. for C₃₁ H₂₈ O₃ S: C, 77.47; H, 5.87. Found: C, 77.35;H, 5.99.

Preparation 4

Prepared in a similar manner employing 4-methoxyphenylboronic acid was[2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]-thiophene ##STR32##

Yield=73%. mp=115-118° C. ¹ H NMR (CDCl₃) _(d) 7.80-7.90 (m, 3H),7.33-7.53 (m, 8H), 6.93-7.06 (m, 6H), 5.00 (s, 2H), 3.83 (s, 3H). FDmass spec: 438. Anal. Calcd. for C₂₈ H₂₂ O₃ S: C, 76.69; H, 5.06. Found:C, 76.52; H, 5.09.

Preparation 5 ##STR33##

To a solution of[2-(4-tertbutyloxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene (1.50g, 3.37 mmol) in 30 mL of absolute ethanol containing 1% concentratedhydrochloric acid was added 0.50 g of 10% palladium-on-carbon. Themixture was hydrogenated at 40 psi for 1 hour, after which the reactionwas judged to be complete by thin layer chromatography. The mixture wasfiltered through a pad of Celite, and the filtrate concentrated invacuo. The crude product was dissolved in minimal ethyl acetate andpassed through a short silicon dioxide column to remove Celite (ethylacetate as eluant). Concentration provided a white solid that wastriturated from hexanes/ethyl ether. Filtration provided 868 mg (73%) of[2-(4-tertbutyloxyphenyl)-3-(4-hydroxy)phenoxy]-benzo[b]thiophene. mp210-213° C. ¹ H NMR (DMSO-d₆) _(d) 9.13 (s, 1H), 7.94 (d, J=7.7 Hz, 1H),7.63 (d, J=8.6 Hz, 2H), 7.35-7.26 (m, 3H), 7.01 (d, J=8.6 Hz, 2H), 6.70(q, J_(AB) =8.9 Hz, 4H), 1.28 (s, 9H). FD mass spec: 390. Anal. Calcd.for C₂₄ H₂₂ O₃ S: C, 73.82; H, 5.68. Found: C, 73.98; H, 5.84.

Preparation 6

Prepared in a similar manner was[2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene ##STR34##

Yield=80%. mp=120-125° C. ¹ H NMR (CDCl₃) _(d) 7.80-7.90 (m, 3H), 7.48(m, 1H), 7.30-7.48 (m, 2H), 6.90-7.03 (m, 4H), 6.76-6.86 (m, 2H), 3.82(s, 3H). FD mass spec: 348; Anal Calcd. for C₂₁ H₁₆ O₃ S: C, 72.39; H,4.63. Found: C, 72.68; H, 4.82.

EXAMPLE 1 ##STR35##

To a solution of [2-(4-tertbutyloxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene (1.25 g, 3.20 mmol) in anhydrousN,N-dimethylformamide (10 mL) at ambient temperature was added cesiumcarbonate (5.70 g, 17.6 mmol). After stirring for 20 minutes,2-chloroethylpiperidine hydrochloride (1.95 g, 10.56 mmol) was added insmall portions. The resulting heterogeneous mixture was stirredvigorously for 24 hours. The contents of the reaction were then dilutedwith water (200 mL). The aqueous phase was extracted with ethyl acetate(3×100 mL). The combined organic layer was then washed with water (2×200mL). Drying of the organic layer (sodium sulfate) and concentration invacuo gave an oil. Chromatography (5-10% methanol/chloroform) provided1.47 g (91%) of3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-tertbutyloxyphenyl)]benzo[b]-thiophenethat was carried on directly to the next step without characterization.

3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-tertbutyloxy-phenyl)]benzo[b]thiophene(1.37 g, 2.73 mmol) was dissolved in triflouroacetic acid (10 mL) atambient temperature. After stirring for 15 minutes, the solvent wasremoved in vacuo. The residue was dissolved in ethyl acetate (20 mL) andwashed with sat. sodium bicarbonate solution (3×10 mL). The organiclayer was dried (sodium sulfate) and concentrated whereupon a whitesolid precipitated formed in solution. The product was recrystallizedfrom ethyl acetate-ethyl ether to provide 1.03 g (85%) of3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiopheneas colorless crystals. mp 169-172° C. ¹ H NMR (DMSO-d₆) _(d) 9.81 (s,1H), 7.93 (d, J=7.7 Hz, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.36-7.26 (m, 3H),6.86 (s, 4H), 6.78 (d, J=8.6 Hz, 2H), 4.10 (m, 2H), 3.29 (m, 2H),2.95-2.75 (m, 4H), 1.68-1.40 (m, 6H). Anal. Calcd. for C₂₇ H₂₇ NO₃S.0.55 CF₃ CO₂ H: C, 66.40; H, 5.46; N, 2.76. Found: C, 65.99; H, 5.49;N, 2.61

EXAMPLE 2 ##STR36##

Data for Example 2 mp 233-240° C. ¹ H NMR (DMSO-d₆) _(d) 10.43 (m, 1H),9.89 (s, 1H), 7.93-7.95 (m, 1H), 7.60-7.64 (m, 2H), 7.35-7.50 (m, 3H),6.83-7.03 (m, 6H), 4.27-4.30 (m, 2H), 3.40-3.60 (m, 4H), 2.96-3.10 (m,2H), 1.70-1.95 (m, 5H), 1.40-1.53 (m, 1H). FD mass spec: 446. Anal.Calcd. for C₂₇ H₂₇ NO₃ S.1.0HCl: C, 67.28; H, 5.86; N, 2.91. Found: C,67,07; H, 5.66; N, 2.96.

EXAMPLE 3

Prepared in an analogous manner were the following examples: ##STR37##

mp 150-155° C. ¹ H NMR (DMSO-d₆) _(d) 9.79 (s, 1H), 7.92 (d, J=7.8 Hz,1H), 7.54 (d, J=8.6 Hz, 2H), 7.36-7.26 (m, 3H), 6.84 (s, 4H), 6.78 (d,J=8.6 Hz, 2H), 4.00 (bt, 2H), 2.92 (m, 2H), 2.85 (m, 4H), 1.73 (m, 4H).Anal. Calcd. for C₂₆ H₂₅ NO₃ S.0.33 CF₃ CO₂ H: C, 68.25; H, 5.44; N,2.99. Found: C, 68.29; H, 5.46; N, 3.19.

EXAMPLE 4 ##STR38##

mp 189-191° C. ¹ H NMR (DMSO-d₆) _(d) 7.91 (d, J=7.6 Hz, 1H), 7.52 (d,J=8.5 Hz, 2H), 7.34-7.25 (m, 3H), 6.81 (s, 4H), 6.75 (d, J=8.6 Hz, 2H),3.89 (bt, 2H), 2.75 (bt, 2H), 2.68 (m, 4H), 1.48 (m, 8H). Anal. Calcd.for C₂₈ H₂₉ NO₃ S.1.50 H₂ O: C, 69.11; H, 6.79; N, 2.88. Found: C,69.25; H, 6.79; N, 2.58.

EXAMPLE 5 ##STR39##

mp 70° C. ¹ H NMR (DMSO-d₆) _(d) 9.91 (bs, 1H), 7.92 (d, J=7.9 Hz, 1H),7.54 (d, J=8.6 Hz, 2H), 7.35-7.24 (m, 3H), 6.82 (s, 4H), 6.78 (d, J=8.6Hz, 2H), 3.88 (bt, 2H), 2.76 (bt, 2H), 2.51 (m, 4H), 0.91 (m, 6H). FDmass spec: 434. Anal. Calcd. for C₂₆ H₂₇ NO₃ S.0.50 H₂ O: C, 70.56; H,6.38; N, 3.16 Found: C, 70.45; H, 6.26; N, 3.20.

EXAMPLE 6 ##STR40##

mp=228-230° C. ¹ H NMR (DMSO-d₆) _(d) 7.96 (d, J=7.5 Hz, 1H), 7.66 (d,J=8.8 Hz, 2H), 7.35-7.50 (m, 3H), 6.98 (d, J=8.7 Hz, 2H), 6.86-6.90 (m,4H), 4.28-4.31 (m, 2H), 3.74 (s, 3H), 3.37-3.45 (m, 4H), 2.92-2.96 (m,2H), 2.46-2.48 (m, 5H), 1.74 (m, 1H). FD mass spec: 459. Anal Calcd. forC₂₈ H₂₉ NO₃ S.1.0HCl: C, 67.80; H, 6.10; N, 2.82. Found: C, 68.06; H, H,6.38; N, 2.60.

Alternate Synthesis of[2-(4-tertbutyloxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophenePreparation 7 ##STR41##

To a -78° C. solution of [3-(4-benzyloxy)phenoxy]benzo[b]-thiophene(5.00 g, 15.1 mmol) in 20 mL of anhydrous tetrahydrofuran under N₂ wasadded n-butyllithium (9.90 mL, 15.8 mmol, 1.6 M in hexanes) dropwise viasyringe. After stirring for 15 minutes, B(OiPr)₃ (3.83 mL, 16.6 mmol)was added via syringe, and the resulting mixture was allowed to warm to0° C. The reaction was then quenched by distributing between ethylacetate and 1.0N hydrochloric acid (100 mL each). The layers wereseparated and the organic was extracted with water (1×100 mL). Theorganic layer was dried (sodium sulfate) and concentrated in vacuo to asolid that was triturated from ethyl ether/hexanes. Filtration provided3.96 g (70%) of [3-(4-benzyloxy)phenoxy]benzo[b]thiophene-2-boronic acidas a white solid. mp 115-121° C. ¹ H NMR (DMSO-d₆) _(d) 8.16 (d, J=8.5Hz, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.42-7.23 (m, 7H), 6.90 (q, J_(AB) =9.0Hz, 4H), 5.01 (s, 2H). Anal. Calcd. for C₂₁ H₁₇ O₄ SB: C, 67 04; H,4.55. Found: C, 67.17; H, 4.78.

[3-(4-Benzyloxy)phenoxy]benzo[b]thiophene-2-boronic acid was reactedwith 4-(-tertbutoxy)bromobenzene according to the conditions describedabove for [2-iodo-3-(4-benzyloxy) phenoxy]-benzo[b]thiophene and4-(tertbutoxy)phenyl boronic acid to give[2-(4-tertbutyloxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene in81% yield.

Examples prepared by employing this method are:

EXAMPLE 7 ##STR42##

mp 223-226° C. ¹ H NMR (DMSO-d₆) _(d) 7.99 (d, J=8.2 Hz, 1H), 7.71 (d,J=7.3 Hz, 1H), 7.44-7.30 (m, 7H), 6.90 (s, 4H), 4.27 (m, 2H), 3.43-3.35(m, 4H), 2.97-2.88 (m, 2H), 1.73-1.61 (m, 5H), 1.34 (m, 1H). Anal.Calcd. for C₂₇ H₂₇ NO₂ S.1.0 HCl: C, 69.59; H, 6.06; N, 3.00. Found: C,69.88; H, 6.11; N, 3.19.

EXAMPLE 8 ##STR43##

mp 219-226° C. ¹ H NMR (DMSO-d₆) _(d) 10.20 (bs, 1H), 7.99 (d, J=8.2 Hz,1H), 7.77-7.73 (m, 4H), 7.42-7.25 (m, 5H), 6.90 (s, 4H), 4.27 (m, 2H),3.44-3.31 (m, 4H), 2.96-2.89 (m, 2H), 1.78-1.61 (m, 5H), 1.34 (m, 1H).FD mass spec: 447. Anal. Calcd. for C₂₇ H₂₆ NO₂ SF.1.0 HCl: C, 67.00; H,5.62; N, 2.89. Found: C, 67.26; H, 5.67; N, 3.03.

Preparation 8

Synthesis of[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene##STR44##

To a solution of [6-methoxy-2-(4-methoxyphenyl)]benzo[b]thiophene (27.0g, 100 mmol) in 1.10 L of chloroform at 60° C. was added bromine (15.98g, 100 mmol) dropwise as a solution in 200 mL of chloroform. After theaddition was complete, the reaction was cooled to room temperature, andthe solvent removed in vacuo to provide 34.2 g (100%) of[6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene as a whitesolid. mp 83-85° C. ¹ H NMR (DMSO-d₆) _(d) 7.70-7.62 (m, 4H), 7.17 (dd,J=8.6, 2.0 Hz, 1H), 7.09 (d, J=8.4 Hz, 2H). FD mass spec: 349, 350.Anal. Calcd. for C₁₆ H₁₃ O₂ SBr: C, 55.03; H, 3.75. Found: C, 54.79; H,3.76.

EXAMPLE 9 ##STR45##

To a solution of[6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene (34.00 g, 97.4mmol) in 60 mL of collidine under N₂ was added 4-benzyloxyphenol (38.96g, 194.8 mmol) and cuprous oxide (14.5 g, 97.4 mmol). The resultantmixture was heated to reflux for 48 hours. Upon cooling to roomtemperature, the mixture was dissolved in acetone (200 mL), and theinorganic solids were removed by filtration. The filtrate wasconcentrated in vacuo, and the residue dissolved in methylene chloride(500 mL). The methylene chloride solution was washed with 3Nhydrochloric acid (3×300 mL), followed by 1N sodium hydroxide (3×300mL). The organic layer was dried (sodium sulfate), and concentrated invacuo. The residue was taken up in 100 mL of ethyl acetate whereupon awhite solid formed that was collected by filtration [recovered[6-methoxy-2-(4-methoxyphenyl)]benzo-[b]thiophene (4.62 g, 17.11 mmol].The filtrate was concentrated in vacuo, and then passed through a shortpad of silica gel (methylene chloride as eluant) to remove baselinematerial. The filtrate was concentrated in vacuo, and the residuecrystallized from hexanes/ethyl acetate to provide initially 7.19 g of[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]-thiopheneas an off-white crystalline solid. The mother liquor was concentratedand chromatographed on silica gel (hexanes/ethyl acetate 80:20) toprovide an additional 1.81 g of product. Total yield of[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophenewas 9.00 g (24% based on recovered starting material). The basic extractwas acidified to pH=4 with 5N hydrochloric acid, and the resultantprecipitate collected by filtration and dried to give 13.3 g ofrecovered 4-benzyloxyphenol. mp 100-103° C. ¹ H NMR (CDCl₃): _(d) 7.60(d, J=8.8 Hz, 2H), 7.39-7.24 (m, 7H), 6.90-6.85 (m, 7H), 4.98 (s, 2H),3.86 (s, 3H) 3.81 (s, 3H). FD mass spec: 468. Anal. Calcd. for C₂₉ H₂₄O₄ S: C, 74.34; H, 5.16. Found: C, 74.64; H, 5.29.

Preparation 9 ##STR46##

To a solution of[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene(1.50 g, 3.20 mmol) in 50 mL of ethyl acetate and 10 mL of 1%concentrated hydrochloric acid in ethanol was added 10%palladium-on-carbon (300 mg). The mixture was hydrogenated at 40 psi for20 minutes, after which time the reaction was judged complete by thinlayer chromatography. The mixture was passed through Celite to removecatalyst, and the filtrate concentrated in vacuo to a white solid. Thecrude product was passed through a pad of silica gel (chloroform aseluant). Concentration provided 1.10 g (91%) of[6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]-thiopheneas a white solid. mp 123-126° C. ¹ H NMR (DMSO-d₆) _(d) 9.10 (s, 1H),7.59 (d, J=8.8 Hz, 2H), 7.52 (d, J=2.1 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H),6.95 (d, J=8.8 Hz, 2H), 6.89 (dd, J=8.8, 2.1 Hz, 1H), 6.72 (d, J=9.0 Hz,2H), 6.63 (d, J=9.0 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H). FD mass spec:378. Anal. Calcd. for C₂₂ H₁₈ O₄ S: C, 69.82; H, 4.79. Found: C, 70.06;H, 4.98.

EXAMPLE 10 ##STR47##

To a solution of[6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)phenoxy]benzo[b]thiophene(1.12 g, 2.97 mmol) in 7 mL of anhydrous N,N-dimethylformamide under N₂was added cesium carbonate (3.86 g, 11.88 mmol). After stirring for 10minutes, 2-chloroethylpiperidine hydrochloride (1.10 g, 1.48 mmol) wasadded. The resultant mixture was stirred for 18 hours at ambienttemperature. The reaction was the distributed between chloroform/water(100 mL each). The layers were separated and the aqueous extracted withchloroform (3×50 mL). The organic was combined and washed with water(2×100 mL). Drying of the organic (sodium sulfate) and concentrationprovided an oil that was chromatographed on silica gel (2%methanol/chloroform). The desired fractions were concentrated to an oilthat was dissolved in 10 mL of ethyl acetate and treated with oxalicacid (311 mg, 3.4 mmol). After stirring for 10 minutes, a whiteprecipitate formed and was collected by filtration and dried to provide1.17 g (70%) overall of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiopheneas the oxalate salt. mp 197-200° C. (dec). ¹ H NMR (DMSO-d₆) _(d) 7.60(d, J=8.7 Hz, 2H), 7.55 (d, J=1.1 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.06(d, J=8.8 Hz, 2H), 6.91 (dd, J=8.8, 1.1 Hz, 1H), 6.87 (s, 4H), 4.19(broad t, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.32 (broad t, 2H), 3.12-3.06(m, 4H), 1.69-1.47 (m, 4H), 1.44-1.38 (m, 2H). FD mass spec: 489. Anal.Calcd. for C₂₉ H₃₁ NO₄ S.0.88 HO₂ CCO₂ H: C, 64.95; H, 5.80; N, 2.46.Found: C, 64.92; H, 5.77; N, 2.54.

EXAMPLE 11 Treatment of Free Base with Ethyl Ether.Hydrochloric AcidProvided[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride ##STR48##

mp 216-220° C. ¹ H NMR (DMSO-d₆) _(d) 10.20 (bs, 1H), 7.64 (d, J=8.7 Hz,2H), 7.59 (d, J=1.5 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 7.00 (d, J=8.7 Hz,1H), 6.96 (dd, J=9.0, 1.5 Hz, 1H), 6.92 (q, J_(AB) =9.0 Hz, 4H), 4.31(m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.43 (m, 4H), 2.97 (m, 2H), 1.77(m, 5H), 1.37 (m, 1H). FD mass spec: 489. Anal. Calcd. for C₂₉ H₃₁ NO₄S.1.0 HCl: C, 66.21; H, 6.13; N, 2.66. Found: C, 66.46; H, 6.16; N,2.74.

Prepared in an analogous manner were the following examples:

EXAMPLE 12 ##STR49##

mp 95-98° C. ¹ H NMR (DMSO-d₆) _(d) 7.64 (d, J=9.0 Hz, 2H), 7.58 (d,J=2.0 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.94 (dd,J=9.0, 2.0 Hz, 1H), 6.86 (s, 4H), 3.97 (t, J=6.0 Hz, 2H), 3.83 (s, 3H),3.76 (s, 3H), 2.73 (t, J=6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 4H). FDmass spec: 477. Anal. Calcd. for C₂₈ H₂₉ NO₄ S: C, 70.71; H, 6.15; N,2.99. Found: C, 70.59; H, 6.15; N, 3.01.

EXAMPLE 13 ##STR50##

mp 189-192° C. ¹ H NMR (DMSO-d₆) _(d) 10.55 (bs, 1H), 7.64 (d, J=9.0 Hz,2H), 7.58 (d, J=2.0 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 7.00 (d, J=9.0 Hz,2H), 6.95 (dd, J=9.0, 2.0 Hz, H), 6.86 (s, 4H), 3.94 (t, J=6.0 Hz, 2H),3.83 (s, 3H), 3.76 (s, 3H), 2.80 (t, J=6.0 Hz, 2H), 2.66 (m, 4H), 1.53(m, 8H). Anal. Calcd. for C₃₀ H₃₃ NO₄ S.1.0 HCl: C, 66.71; H, 6.35; N,2.59. Found: C, 66.43; H, 6.46; N, 2.84.

EXAMPLE 14 ##STR51##

mp 196-198° C. ¹ H NMR (DMSO-d₆) _(d) 10.48 (bs, 1H), 7.64 (d, J=9.0 Hz,2H), 7.59 (d, J=2.0 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 7.00 (d, J=9.0 Hz,2H), 6.97 (dd, J=9.0, 2.0 Hz, 1H), 6.87 (q, J_(AB) =9.0 Hz, 4H), 4.25(m, 2H), 3.83 (s, 3H), 3.77 (s, 3H), 3.54 (m, 2H), 3.09 (m, 4H), 2.00(m, 3H), 1.88 (m, 3H). Anal. Calcd. for C₂₈ H₃₁ NO₄ S.1.5 HCl: C, 63.18;H, 6.15; N, 2.63. Found: C, 63.46; H, 5.79; N, 2.85.

EXAMPLE 15 ##STR52##

mp 208-211° C. ¹ H NMR (DMSO-d₆) _(d) 10.6 (bs, 1H), 7.63 (d, J=9.0 Hz,2H), 7.60 (d, J=2.0 Hz, 1H), 7.20 (J=9.0 Hz, 1H), 7.00 (d, J=9.0 Hz,2H), 6.97 (dd, J=9.0, 2.0 Hz, 1H), 6.91 (q, J_(AB) =9.0 Hz, 4H), 4.29(m., 2H), 4.08-3.91 (m, 4H), 3.82 (s, 3H), 3.77 (s, 3H), 3.59-3.42 (m,4H), 3.21-3.10 (m, 2H). Anal. Calcd. for C₂₈ H₂₉ NO₅ S.1.0 HCl: C,63.09; H, 5.73; N, 2.65. Found: C, 63.39; H, 5.80; N, 2.40.

EXAMPLE 16 ##STR53##

mp 195-200° C. ¹ H NMR (DMSO-d₆) _(d) 9.90 (bs, 1H), 7.64 (d, J=9.0 Hz,2H), 7.59 (d, J=2.0 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 7.00 (d, J=9.0 Hz,2H), 6.95 (dd, J=9.0, 2.0 Hz, 1H), 6.88 (s, 4H), 3.97 (t, J=6.0 Hz, 2H),3.83 (s, 3H), 3.77 (s, 3H), 3.44 (m, 2H), 3.15 (m, 2H), 2.87 (m, 2H),2.12 (m, 2H), 1.77 (m, 5H), 1.39 (m, 1H). Anal. Calcd. for C₃₀ H₃₃ NO₄S.1.15 HCl: C, 66.01; H, 6.40; N, 2.73. Found: C, 66.01; H, 6.40; N,2.73.

EXAMPLE 17 ##STR54##

mp 164-166° C. ¹ H NMR (DMSO-d₆) _(d) 9.77 (bs, 1H), 7.64 (d, J=9.0 Hz,2H), 7.59 (d, J=2.0 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 7.00 (d, J=9.0 Hz,2H), 6.95 (dd, J=9.0, 2.0 Hz, 1H), 6.89 (s, 4H), 3.99 (t, J=6.0 Hz,2H),3.83 (s, 3H), 3.77 (s, 3H), 3.15 (m, 6H), 2.06 (m, 2H), 1.20 (t, J=7.0Hz, 6H). Anal. Calcd. for C₂₉ H₃₃ NO₄ S.1.0 HCl: C, 65.96; H, 6.49; N,2.65. Found: C, 66.25; H, 6.64; N, 2.84.

EXAMPLE 18 ##STR55##

[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride (10.00 g, 19.05 mmol) was dissolved in 500 mL of anhydrousmethylene chloride and cooled to 8° C. To this solution was added borontribromide (7.20 mL, 76.20 mmol). The resultant mixture was stirred at8° C. for 2.5 hours. The reaction was quenched by pouring into astirring solution of saturated sodium bicarbonate (1 L), cooled to 0° C.The methylene chloride layer was separated, and the remaining solidswere dissolved in methanol/ethyl acetate. The aqueous layer was thenextracted with 5% methanol/ethyl acetate (3×500 mL). All of the organicextracts (ethyl acetate and methylene chloride) were combined and dried(sodium sulfate). Concentration in vacuo provided a tan solid that waschromatographed (silicon dioxide, 1-7% methanol/chloroform) to provide7.13 g (81%) of[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]-thiopheneas a white solid. mp 93° C. ¹ H NMR (DMSO-d₆) _(d) 9.73 (bs, 1H), 9.68(bs, 1H), 7.45 (d, J=8.6 Hz, 2H), 7.21 (d, J=1.8 Hz, 1H), 7.04 (d, J=8.6Hz, 1H), 6.84 (dd, J=8.6, 1.8 Hz, 1H (masked)), 6.81 (s, 4H), 6.75 (d,J=8.6 Hz, 2H), 3.92 (t, J=5.8 Hz, 2H), 2.56 (t, J=5.8 Hz, 2H), 2.36 (m,4H), 1.43 (m, 4H), 1.32 (m, 2H). FD mass spec: 462. Anal. Calcd. for C₂₇H₂₇ NO4S: C, 70.20; H, 5.90; N, 3.03. Found: C, 69.96; H, 5.90; N, 3.14.

EXAMPLE 19 ##STR56##

mp 246-249° C. (dec). ¹ H NMR (DMSO-d₆) _(d) 7.45 (d, J=8.6 Hz, 2H),7.22 (d, J=1.8 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 6.87 (dd, J=8.6, 1.8 Hz,1H (masked)), 6.84 (s, 4H), 6.75 (d, J=8.6 Hz, 2H), 4.08 (bt, 2H), 3.01(bt, 2H), 2.79 (m, 4H), 1.56 (m, 4H), 1.40 (m, 2H). FD mass spec 462.Anal. Calcd. for C₂₇ H₂₇ NO₄ S.0.75 HO₂ CCO₂ H: C, 64.63; H, 5.42; N,2.64. Found: C, 64.61; H, 5.55; N, 2.62.

EXAMPLE 20 ##STR57##

mp 158-165° C. ¹ H NMR (DMSO-d₆) _(d) 9.79 (s, 1H), 9.74 (s, 1H), 7.40(d, J=8.6 Hz, 2H), 7.23 (d, J=2.0 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.86(q, J_(AB) =9.3 Hz, 4H), 6.76 (dd, J=8.6, 2.0 Hz, 1), 6.74 (d, J=8.6 Hz,2H), 4.26 (bt, 2H), 3.37 (m, 4H), 2.91 (m, 2H), 1.72 (m, 5 H), 1.25 (m,1H). FD mass spec 461. Anal. Calcd. for C₂₇ H₂₇ NO₄ S.1.0 HCl: C, 65.11;H, 5.67; N, 2.81. Found: C, 64.84; H, 5.64; N, 2.91.

Prepared in an analogous manner were the following examples:

EXAMPLE 21 ##STR58##

mp 99-113° C. ¹ H NMR (DMSO-d₆) _(d) 9.75 (s, 1H), 9.71 (s, 1H), 7.50(d, J=9.0 Hz, 2H), 7.25 (d, J=2.0 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.85(s, 1H), 6.80 (dd, J=9.0, 2.0 Hz, 1H), 6.79 (d, J=9.0 Hz, 2H), 3.93 (m,2H), 2.73 (m, 2H), 2.53 (m, 4H), 0.96 (t, J=7.0 Hz, 4H). Anal. Calcd.for C₂₆ H₂₅ NO₄ S.0.5 H₂ O: C, 68.40; H, 5.74; N, 3.07. Found: C, 68.52;H, 6.00; N, 3.34.

EXAMPLE 22 ##STR59##

mp 125-130° C. ¹ H NMR (DMSO-d₆) _(d) 9.75 (s, 1H), 9.71 (s, 1H), 7.50(d, J=9.0 Hz, 2H), 7.26 (d, J=2.0 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.85(s, 3H), 6.80 (dd, J=9.0, 2.0 Hz, 1H), 6.79 (d, J=9.0 Hz), 3.94 (t,J=6.0 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 2.66 (m, 4H), 1.53 (m, 8H). Anal.Calcd. for C₂₈ H₂₉ NO₄ S: C, 70.71; H, 6.15; N, 2.94. Found: C, 70.67;H, 6.31; N, 2.93.

EXAMPLE 23 ##STR60##

mp 137-141° C. ¹ H NMR (DMSO-d₆) _(d) 9.75 (s, 1H), 9.71 (s, 1H), 7.49(d, J=9.0 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.85(s, 4H), 6.80 (dd, J=9.0, 2.0 Hz, 1H), 6.79 (d, J=9.0 Hz, 2H), 3.95 (t,J=6.0 Hz, 2H), 2.74 (t, J=6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 6H). Anal.Calcd. for C₂₆ H₂₇ NO₄ S: C, 69.46; H, 6.05; N, 3.12. Found: C, 69.76;H, 5.85; N, 3.40.

EXAMPLE 24 ##STR61##

mp 157-162° C. ¹ H NMR (DMSO-d₆) _(d) 10.60 (bs, 1H), 9.80 (s, 1H), 9.75(s, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.28 (d, J=2.0 Hz, 1H), 7.10 (d, J=9.0Hz, 1H), 6.92 (q, J_(AB) =9.0 Hz, 4H), 6.81 (dd, J=9.0, 2.0 Hz, 1H),6.80 (d, J=9.0 Hz, 2H), 4.30 (m, 2H), 3.95 (m, 2H), 3.75 (m, 2H), 3.51(m, 4H), 3.18 (m, 2H). Anal. Calcd. for C₂₆ H₂₅ NO₅ S.HCl: C, 62.46; H,5.24; N, 2.80. Found: C, 69.69; H, 5.43; N, 2.92.

EXAMPLE 25 ##STR62##

mp 185-191° C. ¹ H NMR (DMSO-d₆) _(d) 9.94 (bs, 1H), 9.81 (s, 1H), 9.75(s, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.27 (dd, J=2.0 Hz, 1H), 7.10 (d, J=9.0Hz, 1H), 6.87 (s, 4H), 6.80 (dd, J=9.0, 2.0 Hz, 1H), 6.79 (d, J=9.0 Hz,2H), 3.99 (t, J=6.0 Hz, 2H), 3.14 (m, 6H), 2.08 (m, 2H), 1.20 (t, J=6.0Hz, 6H). Anal. Calcd. for C₂₇ H₂₉ NO₄ S.1.30HCl: C, 63.46; H, 5.98; N,2.74. Found: C, 63.23; H, 6.03; N, 3.14.

EXAMPLE 26 ##STR63##

mp 128-131° C. ¹ H NMR (DMSO-d₆) _(d) 9.81 (bs, 1H), 9.76 (s, 1H), 9.02(s, 1H), 7.49 (d, J=9.0 Hz, 2H), 7.28 (m, 1H), 7.09 (d, J=9.0 Hz, 1H),6.90 (s, 4H), 6.79 (m, 3H), 4.19 (m, 2H), 3.68 (m, 2H), 3.50 (m, 2H).1.31 (m, 12H). Anal. Calcd. for C₂₈ H₃₁ NO₄ S.1.33 HCl: C, 63.92; H,6.19; N, 2.66. Found: C, 63.82; H, 6.53; N, 2.61.

EXAMPLE 27 ##STR64##

mp 258-262° C. ¹ H NMR (DMSO-d₆) _(d) 9.85 (bs, 1H), 9.81 (s, 1H), 9.75(s, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.27 (d, J=2.0 Hz, 1H), 7.10 (d, J=9.0Hz, 1H), 6.87 (s, 4H), 6.80 (dd, J=9.0, 2.0 Hz, 1H), 6.79 (d, J=9.0 Hz,2H), 3.97 (t, J=6.0 Hz, 2H), 3.44 (m, 2H), 3.15 (m, 2H), 2.88 (m, 2H),2.11 (m, 2H), 1.73 (m, 5H), 1.39 (m, 1H). Anal. Calcd. for C₂₈ H₂₉ NO₄S.0.75 HCl: C, 66.87; H, 5.96; N, 2.78. Found: C, 67.04; H, 5.90; N,2.68.

Alternatively, as shown in Scheme III, supra, Example 19 was preparedusing the methoxymethyl (MOM) protecting groups in place of methoxy. Themethods are directly analogous to those just described, with theexception that the MOM groups are removed in the final step by acidhydrolysis.

Preparation 10 ##STR65##

mp 94-96° C. ¹ H NMR (DMSO-d₆) _(d) 7.65 (d, J=2.0 Hz, 1H), 7.64 (d,J=8.6 Hz, 2H), 7.43-7.32 (m, 5H), 7.23 (d, J=8.8 Hz, 1H), 7.08 (d, J=8.6Hz, 2H), 7.04 (dd, J=8.8, 2.0 Hz, 1H), 6.92 (q, J_(AB) =9.2 Hz, 4H),5.26 (s, 2H), 5.21 (s, 2H), 5.01 (s, 3H), 3.40 (s, 3H), 3.37 (s, 3H). FDmass spec 528.

Preparation 11 ##STR66##

mp 90-91° C. ¹ H NMR (DMSO-d₆) _(d) 9.15 (s, 1H), 7.65 (d, J=8.1 Hz,2H), 7.63 (d, J=2.0 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.05 (dd, J=8.8,2.0 Hz, 1H), 6.72 (q, J_(AB) =9.1 Hz, 4H), 5.26 (s, 2H), 5.21 (s, 2H),3.40 (s, 3H), 3.37 (s, 3H). FD mass spec 438. Anal. Calcd. for C₂₄ H₂₂O₆ S: C, 65.74; H, 5.06. Found: C, 65.50; H, 4.99.

EXAMPLE 28 ##STR67##

To a solution of[6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene (10.0 g, 28.6mmol) in 50 mL of anhydrous methylene chloride was added 50 mL oftriflouroacetic acid. After stirring for 5 minutes, hydrogen peroxide(4.0 mL, 28.6 mmol, 30% aqueous solution) was added. The resultingmixture was stirred at ambient temperature for 2 hours. Solid sodiumbisulfite (1.25 g) was added to the dark solution followed by 15 mL ofwater. The mixture was stirred vigorously for 15 minutes thenconcentrated in vacuo. The residue was partitioned between chloroformsaturated sodium bicarbonate solution (200 mL ea.). The layers wereseparated and the organic layer was extracted with saturated sodiumbicarbonate solution. The organic layer was then dried (sodium sulfate)and concentrated in vacuo to a solid that was triturated from ethylether/ethyl acetate. Filtration provided 8.20 g (80%) of[6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide) as ayellow solid that can be recrystallized from ethyl acetate. m.p.170-173° C. ¹ H NMR (DMSO-d₆) _(d) 7.24 (d, J=2.2 Hz, 1H), 7.68 (d,J=8.8 Hz, 2H), 7.54 (d, J=8.5 Hz, 1H), 7.26 (dd, J=8.5, 2.2 Hz, 1H),7.10 (d, J=8.8 H, 2H), 3.86 (s, 3H), 3.80 (s, 3H). Anal. Calcd. for C₁₆H₁₃ O₃ SBr: C, 52.62; H, 3.59. Found: C, 52.40; H, 3.55.

EXAMPLE 29

Prepared in an analogous manner was[2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide). ##STR68##

mp 120-125° C. ¹ H NMR (DMSO-d₆) _(d) 8.06 (d, J=7.6 Hz, 1H), 7.78-7.59(m, 5H), 7.13 (d, J=8.7 Hz, 2H), 3.81 (s, 3H). FD mass spec: 335. Anal.Calcd. for C₁₅ H₁₁ O₂ SBr: C, 53.75; H, 3.31. Found: C, 53.71; H, 3.46.

Preparation 12

Preparation of 4-(2-(1-piperidinyl)ethoxy)-phenol. ##STR69##

To a solution of 4-benzyloxyphenol (50.50 g, 0.25 mol) in 350 mL ofanhydrous DMF was added 2-chloroethylpiperidine (46.30 g, 0.25 mol).After stirring for 10 minutes, potassium carbonate (52.0 g, 0.375 mol)and cesium carbonate (85.0 g, 0.25 mol) were added. The resultingheterogeneous mixture was stirred vigorously at ambient temperature for48 hours. The reaction was then poured into water (500 mL) and extractedwith methylene chloride. The organic was then extracted with 1 N sodiumhydroxide several times and finally washed with brine. The organic layerwas then dried (sodium sulfate) and concentrated in vacuo to an oil.Chromatography (SiO₂, 1:1 hexanes/ethyl acetate) provided 60.0 g (77%)of 4-[2-(1-piperidinyl)ethoxy]phenoxybenzyl ether as a colorless oil. ¹H NMR (DMSO-d₆) _(d) 7.40-7.27 (m, 5H), 6.84 (q, J_(AB) =11.5 Hz, 4H),4.98 (s, 2H), 3.93 (t, J=6.0 Hz, 2H), 2.56 (t, J=6.0 Hz, 2H), 2.35-2.37(m, 4H), 1.48-1.32 (m, 6H). FD mass spec: 311. Anal. Calcd. for C₂₀ H₂₅NO₂ : C, 77.14; H, 8.09; N, 4.50. Found: C, 77.34; H, 8.18; N, 4.64.

4-[2-(1-Piperidinyl)ethoxy]phenoxybenzyl ether (21.40 g, 68,81 mmol) wasdissolved in 200 mL of 1:1 EtOH/EtOAc containing 1% con. HCl. Thesolution was transferred to a Parr bottle, and 5% palladium-on-carbon(3.4 g) was added. The mixture was hydrogenated at 40 psi for 2 hours.The mixture was then passed through a plug of Celite to remove catalyst.The filtrate was concentrated in vacuo to a solid that was slurried inethyl ether and filtered to provide 12.10 g (83%) of4-(2-(1-piperidinyl)ethoxy]-phenol. mp 148-150° C. ¹ H NMR (DMSO-d₆)_(d) 8.40 (s, 1H), 6.70 (q, J_(AB) =11.5 Hz, 4H), 3.93 (t, J=6.0 Hz,2H), 2.59 (t, J=6.0 Hz, 2H), 2.42-2.38 (m, 4H), 1.52-1.32 (m, 6H). FDmass spec: 221. Anal. Calcd. for C₁₃ H₁₉ NO₂ : C, 70.56; H, 8.09; N,4.50. Found: C, 70.75; H, 8.59; N, 6.54.

EXAMPLE 30 ##STR70##

To a solution of 4-(2-(1-piperidinyl)ethoxy)-phenol (0.32 g, 1.43 mmol)in 5 mL of anhydrous DMF at ambient temperature was added sodium hydride(0.57 g, 1.43 mmol, 60% dispersion in mineral oil). After stirring for15 minutes,[6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide) (0.50g, 1.37 mmol) was added in small portions. After stirring for 1 hour,the reaction was judged complete by TLC analysis. The solvent wasremoved in vacuo, and the residue was distributed between water and 10%ethanol/ethyl acetate. The organic was washed several times with waterand then dried (sodium sulfate). Concentration in vacuo gave an oil thatwas triturated from ethyl acetate/hexanes to provide 0.62 g (89%) of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)as a light yellow solid. mp 97-100° C. ¹ H NMR (DMSO-d₆) _(d) 7.68 (d,J=2.1 Hz, 1H), 7.62 (d, J=8.8 Hz, 2H), 7.06-6.92 (m, 6H), 6.85 (d, J=8.8Hz, 2H), 3.94 (t, J=6.0 Hz, 2H), 3.81 (s, 3H), 3.72 (s, 3H), 2.56 (t,J=6.0 Hz, 2H), 2.39-2.32 (m, 4H), 1.47-1.32 (m, 6H). Anal. Calcd. forC₂₉ H₃₁ NO₅ S: C, 68.89; H, 6.18; N, 2.77. Found: C, 68.95; H, 6.04; N,2.57.

EXAMPLE 31

Prepared in an analogous manner was[3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)##STR71##

Oil. ¹ H NMR (DMSO-d₆) _(d) 8.03 (m, 1H), 7.65 (d, J=8.7 Hz, 2H),7.53-7.50 (m, 2H), 7.09-6.82 (m, 7H), 3.94 (bt, J=5.9 Hz, 2H), 3.74 (s,3H), 2.56 (bt, J=5.9 Hz, 2H), 2.36-2.33 (m, 4H), 1.45-1.31 (m, 6H). FDmass spec: 475. Anal. Calcd. for C₂₈ H₂₉ NO₄ S: C, 70.71; H, 6.15; N.2.94. Found: C, 70.44; H, 6.43; N, 3.20.

EXAMPLE 32 ##STR72##

To a solution of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)(Example 30) (3.00 g, 5.94 mmol) in 200 mL of anhydrous THF undernitrogen gas at 0° C. was added lithium aluminum hydride (0.34 g, 8.91mmol) in small portions. After stirring for 30 minutes, the reaction wasquenched by the careful addition of 5.0 mL of 2.0 N sodium hydroxide.The mixture was stirred vigorously for 30 minutes, and additional 2.0 Nsodium hydroxide was added to dissolve salts. The mixture was thendistributed between water and 10% sodium hydroxide. The layers wereseparated and the aqueous extracted several times with 10% ethanol/ethylacetate. The organic layer was dried (sodium sulfate) and concentratedin vacuo to an oil. The crude product was dissolved in 50 mL of 1:1ethyl acetate/ethyl ether and treated with excess ethyl etherhydrochloride. The resulting precipitate was collected and dried toprovide 2.98 g (96%) of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride as a white solid.

Example 6 was also prepared from Example 31 by the same procedure.

Preparation 13 ##STR73##

To a solution of 6-methoxybenzo[b]thiophene (18.13 g, 111 mol) in 150 mLof anhydrous tetrahydrofuran (THF) at -60° C. was added n-butyllithium(76.2 mL, 0.122 mol, 1.6 M solution in hexanes), dropwise via syringe.After stirring for 30 minutes, triisopropyl borate (28.2 mL, 0.122 mol)was introduced via syringe. The resulting mixture was allowed togradually warm to 0° C. and then distributed between 1N hydrochloricacid and ethyl acetate (300 mL each). The layers were separated, and theorganic layer was dried over sodium sulfate. Concentration in vacuoproduced a white solid that was triturated from ethyl ether hexanes.Filtration provided 16.4 g (71%) of 6-methoxybenzo[b]thiophene-2-boronicacid as a white solid. mp 200° C. (dec). ¹ H NMR (DMSO-d₆) _(d) 7.83 (s,1H), 7.78 (d, J=8.6 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 6.97 (dd, J=8.6,2.0 Hz, 1H), 3.82 (s, 3H). FD mass spec: 208.

Preparation 14 ##STR74##

To a solution of 6-methoxybenzo[b]thiophene-2-boronic acid (3.00 g, 14.4mmol) in 100 mL of toluene was added 4-(methanesulfonyloxy)phenylbromide(3.98 g, 15.8 mmol) followed by 16 mL of 2.0 N sodium carbonatesolution. After stirring for 10 minutes,tetrakistriphenylphosphinepalladium (0.60 g, 0.52 mmol) was added, andthe resulting mixture was heated to reflux for 5 hours. The reactionmixture was then allowed to cool to ambient temperature whereupon theproduct precipitated from the organic phase. The aqueous phase wasremoved and the organic layer was concentrated in vacuo to a solid.Trituration from ethyl ether yielded a solid that was filtered and driedin vacuo to provide 3.70 g (77%) of[6-methoxy-2-(4-methanesulfonyloxy-phenyl)]benzo[b]thiophene as a tansolid. mp 197-201° C. ¹ H NMR (DMSO-d₆) _(d) 7.82-7.77 (m, 3H), 7.71 (d,J=8.8 Hz, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.40 (d, J=8.7 Hz, 2H), 6.98 (dd,J=8.7, 1.5 Hz, 1H), 3.80, (s, 3H), 3.39 (s, 3H). FD mass spec 334. Anal.Calcd. for C₁₆ H₁₄ O₄ S₂ : C, 57.46; H, 4.21. Found: C, 57.76; H, 4.21.

Preparation 15

Prepared in an analogous manner to Preparation 14 was[6-methoxy-2-(4-benzyloxyphenyl)]benzo[b]thiophene ##STR75##

Yield=73%. mp 217-221° C. ¹ H NMR (DMSO-d₆) _(d) 7.63-7.60 (m, 3H),7.59-7.26 (m, 7H), 7.02 (d, J=8.7 Hz, 2H), 6.96 (dd, J=8.8, 2.2 Hz, 1H),5.11 (s, 2H), 3.88 (s, 3H). FD mass spec 346. Anal. Calcd. for C₂₂ H₁₈O₂ S: C, 76.27; H, 5.24. Found: C, 76.00; H, 5.25.

Preparation 16 ##STR76##

To a solution of[6-methoxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene (9.50 g,28.40 mmol) in anhydrous methylene chloride (200 mL) at room undernitrogen gas was added boron tribromide (14.20 g, 5.36 mL, 56.8 mmol).The resulting mixture was stirred at ambient temperature for 3 hours.The reaction was quenched by slowly pouring into excess ice water. Aftervigorously stirring for 30 minutes, the white precipitate was collectedby filtration, washed several times with water, and then dried in vacuoto provide 8.92 g (98%) of[6-hydroxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene as a whitesolid. mp 239-243° C. ¹ H NMR (DMSO-d₆) _(d) 9.70 (s, 1H), 7.76 (d,J=8.7 Hz, 2H), 7.72 (s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.38 (d, J=8.7 Hz,2H), 7.24 (d, J=1.7 Hz, 1H), 6.86 (dd, J=8.7, 1.7 Hz, 1H), 3.38 (s, 3H).FD mass spec 320. Anal. Calcd. for C₁₅ H₁₂ O₄ S₂ : C, 56.23; H, 3.77.Found: C, 56.49; H, 3.68.

Preparation 17 ##STR77##

To a solution of [6-hydroxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene (3.20 g, 10.0 mmol) in 75 mL of anhydrous DMFwas added Cs₂ CO₃ (5.75 g, 17.7 mmol) followed by benzylchloride (1.72mL, 11.0 mmol). The resulting mixture was stirred vigorously for 24hours. The solvent was removed in vacuo, and the solid residue wassuspended in 200 mL of water. The white precipitate was collected byfiltration and washed several times with water. Upon drying in vacuo,the crude product was suspended in 1:1 hexanes:ethyl ether. The solidwas collected to provide 3.72 g (91%) of[6-benzyloxy-2-(4-methanesulfonyloxy-phenyl)]benzo[b]thiophene as awhite solid. mp 198-202° C. ¹ H NMR (DMSO-d₆) _(d) 7.81-7.78 (m, 3H),7.72 (d, J=8.7 Hz, 1H), 7.64 (d, J=2.2 Hz, 1H), 7.47-7.30 (m, 7H), 5.15(s, 2H), 3.39 (s, 3H). FD mass spec 410.

Preparation 18 ##STR78##

To a solution of[6-benzyloxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]thiophene (12.50 g,30.50 mmol) in 300 mL of anhydrous THF under nitrogen gas at ambienttemperature was added lithium aluminum hydride (2.32 g, 61.0 mmol) insmall portions. The mixture was then stirred at ambient temperature for3 hours and then quenched by carefully pouring the mixture into anexcess of cold 1.0 N hydrochloric acid. The aqueous phase was extractedwith ethyl acetate. The organic was then washed several times with waterand then dried (sodium sulfate) and concentrated in vacuo to a solid.Chromatography (silicon dioxide, chloroform) provided 8.75 g (87%) of[6-benzyloxy-2-(4-hydroxyphenyl)]benzo[b]thiophene as a white solid. mp212-216° C. ¹ H NMR (DMSO-d₆) _(d) 9.70 (s, 1H), 7.63 (d, J=8.7 Hz, 1H),7.56 (d, J=2.2 Hz, 1H), 7.51-7.30 (m, 8H), 7.00 (dd, J=8.7, 2.2 Hz, 1H),6.80 (d, J=8.6 Hz, 2H), 5.13 (s, 2H). FD mass spec 331. Anal. Calcd. forC₂₁ H16O₂ S: C, 75.88; H, 4.85. Found: C, 75.64; H, 4.85.

EXAMPLE 19 ##STR79##

To a solution of [6-benzyloxy-2-(4-hydroxyphenyl)]benzo[b]thiophene(8.50 g, 26.40 mmol) in 200 mL of anhydrous DMF under nitrogen gas atambient temperature was added sodium hydride (1.66 g, 41.5 mmol) insmall portions. Once gas evolution had ceased, iodomethane (3.25 mL,52.18 mmol) was added dropwise. The reaction was stirred for 3 hours atambient temperature. The solvent was then removed in vacuo, and theresidue distributed between water/ethyl acetate. The layers wereseparated, and the organic phase was washed several times with water.The organic layer was then dried (sodium sulfate) and concentrated invacuo to provide 9.00 g (98%) of[6-benzyloxy-2-(4-methoxyphenyl)]benzo[b]thiophene as a white solid. mp180-185° C. ¹ H NMR (DMSO-d₆) _(d) 7.67-7.58 (m, 5H), 7.46-7.29 (m, 5H),7.02 (dd, J=8.8, 2.2 Hz, 1H), 6.98 (d, J=8.7 Hz, 2H), 5.13 (s, 2H), 3.76(s, 3H). FD mass spec 346. Anal. Calcd. for C₂₂ H₁₈ O₂ S: C, 76.27; H,5.24. Found: C, 76.54; H, 5.43.

Preparation 20 ##STR80##

[6-Benzyloxy-2-(4-methoxyphenyl)]benzo[b]thiophene (10.0 g, 28.9 mmol)was placed in 200 mL of chloroform along with 10.0 g of solid sodiumbicarbonate at ambient temperature. To this suspension was added bromine(1.50 mL, 29.1 mmol) dropwise over 30 minutes as a solution in 100 mL ofchloroform. Upon completion of the addition, water (200 mL) was addedand the layers were separated. The organic phase was dried (sodiumsulfate) and concentrated in vacuo to a white solid. Crystallizationfrom methylene chloride/methanol provided 10.50 g (85%) of[6-benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo-[b]thiophene as a whitesolid. mp 146-150° C. ¹ H NMR (DMSO-d₆) _(d) 7.70 (d, J=2.2 Hz, 1H),7.65-7.60 (m, 3H), 7.47-7.30 (m, 5H), 7.19 (dd, J=8.8, 2.2 Hz, 1H), 7.06(d, J=8.7 Hz, 2H), 5.17 (s, 2H), 3.78 (s, 3H). FD mass spec 346. Anal.Calcd. for C₂₂ H₁₇ O₂ SBr: C, 62.13; H, 4.03. Found: C, 61.87; H, 4.00.

Preparation 21

Prepared in an analogous manner was[6-methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo-[b]thiophene ##STR81##

Yield=91%. mp 125-127° C. ¹ H NMR (DMSO-d₆) _(d) 7.64-7.61 (m, 4H),7.46-7.31 (m, 5H), 7.15-7.09 (m, 3H), 5.15 (s, 2H), 3.82 (s, 3H). FDmass spec 346. Anal. Calcd. for C₂₂ H₁₇ O₂ SBr: C, 62.13; H, 4.03.Found: C, 62.33; H, 3.93.

Prepared in a manner analgous to Example 28 are Examples 33-34.

EXAMPLE 33 ##STR82##

Isolated as a yellow solid by crystallization from ethyl acetate. mp202-205° C. ¹ H NMR (DMSO-d₆) _(d) 7.80 (d, J=2.2 Hz, 1H), 7.68 (d,J=8.7 Hz, 2H), 7.55 (d, J=8.4 Hz, 1H) 7.47-7.32 (m, 6H), 7.10 (d, J=8.7Hz, 2H), 5.23 (s, 2H), 3.80 (s, 3H). FD mass spec 441. Anal. Calcd. forC₂₂ H₁₇ O₃ SBr: C, 59.87; H, 3.88. Found: C, 59.59; H, 3.78.

EXAMPLE 34 ##STR83##

Isolated as a yellow solid by chromatography (SiO₂, CHCl₃). mp 119-123°C. ¹ H NMR (DMSO-d₆) _(d) 7.73 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.8 Hz,2H), 7.55 (d, J=8.5 Hz, 1H) 7.46-7.31 (m, 5), 7.26 (dd, J=8.5, 2.2 Hz,1H), 7.18 (d, J=8.8 Hz, 2H), 5.16 (s, 2H), 3.86 (s, 3H). FD mass spec441. Anal. Calcd. for C₂₂ H₁₇ O₃ SBr: C, 59.87; H, 3.88. Found: C,60.13; H, 4.10.

Prepared in a manner analagous to Example 30 are Examples 35-36.

EXAMPLE 35 ##STR84##

Yellow oil. ¹ H NMR (DMSO-d₆) _(d) 7.76 (d, J=2.2 Hz, 1H), 7.62 (d,J=8.8 Hz, 2H), 7.44-7.30 (m, 5H), 7.12 (dd, J=8.6, 2.2 Hz, 1H),7.03-6.93 (m, 5H), 6.85 (d, J=8.8 Hz, 2H), 5.18 (s, 2H), 3.94 (bt, J=5.8Hz, 2H), 3.73 (s, 3H), 2.56 (bt, J=5.8 Hz, 2H), 2.37-2.34 (m, 4H),1.45-1.32 (m, 6H). FD mass spec 592. Anal. Calcd. for C₃₅ H₃₅ NO₅ S: C,72.26; H, 6.06; N, 2.41. Found: C, 72.19; H, 5.99; N, 2.11.

EXAMPLE 36 ##STR85##

Yellow solid. mp 89-93° C. ¹ H NMR (DMSO-d₆) _(d) 7.68 (d, J=2.2 Hz,1H), 7.62 (d, J=8.8 Hz, 2H), 7.42-7.28 (m, 5H), 7.08-6.92 (m, 6H), 6.86(d, J=8.8 Hz, 2H), 5.09 (s, 2H), 3.94 (bt, J=5.8 Hz, 2H), 3.81 (s, 3H),2.56 (bt, J=5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.45-1.31 (m, 6H). FD massspec 592. Anal. Calcd. for C₃₅ H₃₅ NO₅ S.0.25 EtOAc: C, 71.62; H, 6.18;N, 2.32. Found: C, 71.32; H, 5.96; N, 2.71.

Prepared in a manner analagous to Example 11 are Examples 37-38.

EXAMPLE 37 ##STR86##

Isolated in 95% overall yield starting from[6-benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide).Purified by chromatography (SiO₂, 1-5% methanol/chloroform) to providean off-white solid. mp 105-108° C. ¹ H NMR (DMSO-d₆) _(d) 7.62 (d, J=2.2Hz, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.45-7.30 (m, 5H), 7.15 (dd, J=8.6 Hz,1H), 7.00-6.94 (m, 3H), 6.82 (s, 4H), 5.13 (s, 2H), 3.92 (bt, J=5.8 Hz,2H), 3.72 (s, 3H), 2.55 (bt, J=5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.44-1.31(m, 4H). FD mass spec 565. Anal. Calcd. for C₃₅ H₃₅ NO₄ S: C, 74.31; H,6.24; N, 2.48. Found: C, 74.35; H, 6.07; N, 2.76.

EXAMPLE 38 ##STR87##

Yield=91%. mp 106-110° C. ¹ H NMR (DMSO-d₆) _(d) 7.59 (d, J=8.8 Hz, 2H),7.54 (d, J=2.2 Hz, 1H), 7.42-7.28 (m, 5H), 7.13 (d, J=8.8 Hz, 1H), 7.03(d, J=8.8 Hz, 2H), 6.82 (s, 4H), 5.08 (s, 2H), 3.92 (bt, J=5.8 Hz, 2H),3.78 (s, 3H), 2.55 (bt, J=5.8 Hz, 2H), 2.37-2.33 (m, 4H), 1.44-1.31 (m,4H). FD mass spec 565. Anal. Calcd. for C₃₅ H₃₅ NO₄ S: C, 74.31; H,6.24; N, 2.48. Found: C, 74.26; H, 6.17; N, 2.73.

EXAMPLE 39 ##STR88##

To a solution of[6-benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene(8.50 g, 15.0 mmol) in 300 mL of 5:1 ethanol/ethyl acetate was addedpalladium black (1.50 g), ammonium formate (3.50 g, 55.6 mmol), and 30mL of water. The resulting mixture was heated to reflux and monitored byTLC. After approximately 3 hours, the reaction was judged complete andthe solution was cooled to ambient temperature. The reaction wasfiltered through a pad of Celite to remove catalyst, and the filtratewas concentrated in vacuo to a solid. The concentrate was distributedbetween saturated sodium bicarbonate solution and 5% ethanol/ethylacetate. The layers were separated, and the organic phase was dried(sodium sulfate) and concentrated in vacuo. The crude product waschromatographed (silicon dioxide, 1-5% methanol/chloroform) to provide6.50 g (91%) of[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiopheneas foam that converted to solid upon trituration with hexanes. mp174-176° C. ¹ H NMR (DMSO-d₆) _(d) 9.77 (s, 1H), 7.56 (d, J=8.8 Hz, 2H),7.23 (d, J=2.0 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H),6.81 (s, 4H), 6.76 (dd, J=8.6, 2.0 Hz, 1H), 3.91 (bt, J=5.9 Hz, 2H),3.71 (s, 3H), 2.55 (bt, J=5.9 Hz, 2H), 2.38-2.33 (m, 4H), 1.46-1.28 (m,6H). FD mass spec 475. Anal. Calcd. for C₂₈ H₂₉ NO₄ S: C, 70.71; H,6.15; N, 2.94. Found: C, 70.46; H, 5.93; N, 2.71.

EXAMPLE 40

Prepared in an analogous manner to Example 39 was[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxyl-2-(4-hydroxyphenyl)]benzo[b]thiophene##STR89##

Yield=88%. mp 147-150° C. ¹ H NMR (DMSO-d₆) _(d) 9.72 (s, 1H), 7.51 (d,J=2.0 Hz, 1H), 7.48 (d, J=8.6 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 6.88 (dd,J=8.8, 2.2 Hz, 1H), 6.81 (s, 4H), 6.76 (d, J=8.6, 2H), 3.91 (bt, J=5.9Hz, 2H), 3.77 (s, 3H), 2.55 (bt, J=5.9 Hz, 2H), 2.38-2.33 (m, 4H),1.46-1.28 (m, 6H). FD mass spec 475. Anal. Calcd. for C₂₈ H₂₉ NO₄ S: C,70.71; H, 6.15; N, 2.94. Found: C, 71.00; H, 6.17; N, 2.94.

Alternatively, Examples 39 and 40 can be prepared by the same transferhydrogenolysis procedure directly in 90% yield from[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-benzyloxyphenyl)]benzo[b]thiophene-(S-oxide)and[6-benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide),respectively.

EXAMPLE 41 ##STR90##

mp 156-160° C. ¹ H NMR (DMSO-d₆) _(d) 10.28 (bs, 1H), 9.85 (s, 1H), 7.56(d, J=8.8 Hz, 2H), 7.25 (d, J=2.0 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 6.93(d, J=8.8 Hz, 2H), 6.87 (q, J_(AB) =9.3 Hz, 4H), 4.27 (bt, J=5.9 Hz,2H), 3.71 (s, 3H), 3.44-3.31 (m, 4H), 2.98-2.88 (m, 2H), 1.74-1.60 (m,5H), 1.36-1.29 (m, 1H) FD mass spec 475. Anal. Calcd. for C₂₈ H₂₉ NO₄S.1.0 HCl: C, 65.68; H, 5.90; N, 2.73. Found: C, 65.98; H, 6.11; N,2.64.

EXAMPLE 42

Prepared in a manner analogous to Example 41 was(6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride ##STR91##

mp 215-217° C. ¹ H NMR (DMSO-d₆) _(d) 10.28 (bs, 1H), 9.80 (s, 1H), 7.52(d, J=2.2 Hz, 1H), 7.47 (d, J=8.6 Hz, 2H), 7.12 (d, J=8.4 Hz, 1H),6.91-6.80 (m, 5H), 6.78 (d, J=8.6 Hz, 2H), 4.27 (bt, J=5.8 Hz, 2H), 3.78(s, 3H), 3.43-3.34 (m, 4H), 2.97-2.91 (m, 2H), 1.78-1.61 (m, 5H),1.36-1.29 (m, 1H), FD mass spec 475. Anal. Calcd. for C₂₈ H₂₉ NO₄ S.1.0HCl: C, 65.68; H, 5.90; N, 2.73. Found: C, 65.87; H, 5.79; N, 2.99.

EXAMPLE 43 ##STR92##

To a solution of Example 20 (0.50 g, 1.08 mmol) in 20 mL of anhydroustetrahydrofuran at 0° C. was added triethylamine (1.00 mL). To thismixture was added benzoylchloride (0.28 mL, 2.35 mmol). After stirringat 0° C. for 2 hours, the reaction was quenched by distributing betweenethyl acetate/saturated sodium bicarbonate solution (100 mL each). Thelayers were separated and the organic was dried (sodium sulfate) andconcentrated in vacuo to a white solid. The crude product was dissolvedin 10 mL of ethyl acetate and treated with ethyl ether.hydrochloricacid. A white precipitate formed that was collected by filtration.Drying provided 390 mg (50%) of[6-benzoyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-benzoyloxyphenyl)]benzo[b]thiophene hydrochloride as a white solid. mp 200-204° C. ¹ H NMR(DMSO-d₆) _(d) 9.95 (bs, 1H), 8.18 (m, 1H), 8.16 (m, 2H), 8.12 (dd,J=10.0, 2.0 Hz, 2H), 7.87 (dd, J=7.0, 2.0 Hz, 2H), 7.78 (m, 2H), 7.64(m, 2H), 7.42 (d, J=7.0 Hz, 2H), 7.34 (dd, J=8.0, 2.0 Hz, 1H), 7.00 (s,4H), 4.32 (m, 2H), 3.45 (m, 4H), 2.99 (m, 2H), 1.75 (m, 5H), 1.39 (m,1H). Anal. Calcd. for C₄₁ H₃₅ NO₆ S.1.5HCl: C, 67.97; H, 5.08; N, 1.93.Found: C, 68.05; H, 5.24; N, 2.01.

By the same procedure was prepared:

EXAMPLE 44 ##STR93##

Yield=72%. mp 110-115° C. ¹ H NMR (DMSO-d₆) _(d) 10.15 (bs, 1H), 8.15(d, J=2.0 Hz, 1H), 7.85 (d, J=7.0 Hz, 2H), 7.43 (m, 3H), 7.34 (dd,J=9.0, 2.0 Hz, 1H), 6.97 (m, 4H), 4.31 (m, 2H), 3.57 (m, 4H), 3.44 (m,4H), 2.97 (m, 2H), 1.76 (m, 5H), 1.40 (m, 7H). Anal. Calcd. for C₃₁ H₃₅NO₈ S₃.1.5HCl: C, 54.57; H, 5.32; N, 2.05. Found: C, 54.36; H, 5.37; N,2.05.

By a similar procedure employing triflouromethanesulfonic anhydride was:

EXAMPLE 45 ##STR94##

Yield=81%. Oil. ¹ H NMR (DMSO-d₆) _(d) 7.82 (d, J=8.7 Hz, 2H), 7.60 (d,J=2.0 Hz, 1H), 7.54 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.8 Hz, 1H), 6.93 (dd,J=8.8, 2.0 Hz, 1H), 6.84 (s, 4H), 3.92 (bt, J=5.7 Hz, 2H), 3.79 (s, 3H),2.56 (bt, J=5.7 Hz, 2H), 2.36-2.30 (m, 4H), 1.44-1.31 (m, 6H). FD massspec: 607. Anal. Calcd. for C₂₉ H₂₈ NO₆ F₃ S₂ : C, 57.32; H, 4.64; N,2.30. Found: C, 57.16; H, 4.52; N, 2.01.

Prepared from Example 1 by similar procedures were:

EXAMPLE 46 ##STR95##

Yield=85%. mp 190-198° C. ¹ H NMR (DMSO-d₆) _(d) 10.48 (br s, 1H),8.00-8.10 (m, 2H), 7.80-8.00 (m, 3H), 7.60-7.53 (m, 4H), 7.40-7.56 (m,6H), 6.93 (s, 2H), 4.37-4.43 (m, 2H), 3.00-3.05 (m, 2H), 2.53-2.63 (m,6H), 1.75-1.95 (m, 3H), 1.40-1.50 (m, 1H). FD mass spec: 550. Anal.Calcd. for C₃₄ H₃₁ NO₄ S.1.0HCl: C, 74.29; H, 5.68; N, 2.55. Found: C,74.52; H, 5.80; N, 2.59.

EXAMPLE 47 ##STR96##

Yield=90%. mp=193-197° C. ¹ H NMR (DMSO-d₆) _(d) 10.10 (br s, 1H), 8.12(d, J=8.0 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.40-7.53 (m, 3H), 7.15 (d,J=6.7 Hz, 2 H), 7.00 (s, 5H), 4.33-4.40 (m, 2H), 3.45-3.60 (m, 4H),3.00-3.10 (m, 2H), 1.70-1.90 (m, 6H), 1.40 (s, 9H). FD mass spec: 529.Anal. Calcd. for C₃₂ H₃₅ NO₄ S.1.0HCl: C, 67.89; H, 6.41; N, 2.47.Found: C, 68.94; H, 6.61; N, 1.72.

EXAMPLE 48 ##STR97##

Yield=85% white solid. mp=98-104° C. ¹ H NMR (DMSO-d₆) _(d) 10.20 (br s,1H), 8.02 (d, J=8.0 Hz, 1H), 7.82 (d, J=8.7 Hz, 2H), 7.40-7.55 (m, 2H),7.00 (s, 4H), 4.30-4.40 (m, 2H), 3.46-3.66 (m, 6H), 3.00-3.10 (m, 2H),1.70-1.95 (m, 6H), 1.40-1.60 (m, 4H), 0.87 (t, J=7.3 Hz, 3H). FD massspec: 565. Anal. Calcd. for C₃₁ H₃₅ NO₅ S₂.1.0HCl: C, 61.83; H, 6.03; N,2.33. Found: C, 61.55; H, 6.15; N, 2.25.

Preparation 21 ##STR98## Preparation of4-(methoxymethyloxy)phenyldisulfide.

To a solution of 4-hydroxyphenyldisulfide (650 mg, 2.60 mmol) in 10 mLof anhydrous N,N-dimethylformamide at 10° C. was added sodium hydride(230 mg, 5.75 mmol, 60% dispersion in mineral oil). After stirring for15 minutes, chloromethylmethyl ether (0.44 mL, 5.75 mmol) was added viasyringe. The reaction was warmed to ambient temperature and stirred for0.5 hours. The mixture was distributed between brine/ethyl acetate (20mL each). The layers were separated and the aqueous phase extracted withethyl acetate (2×20 mL). The organic was dried (sodium sulfate) andconcentrated to a yellow oil (993 mg, 100%). An analytical sample of4-(methoxymethyloxy)-phenyldisulfide was prepared by chromatography(silicon dioxide, 4% ethyl acetate/hexanes). ¹ H NMR (DMSO-d₆) _(d) 7.40(d, J=6.9 Hz, 4H), 7.00 (d, J=6.9 Hz, 4H), 5.15 (s, 4H), 3.32 (s, 6H).FD mass spec: 338. Anal. Calcd. for C₁₆ H₁₈ O₄ S₂ : C, 56.78; H, 5.36.Found: C, 57.08; H, 5.44.

EXAMPLE 49 ##STR99##

To a solution of[6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene (1.82 g, 5.2mmol) in 10 mL of anhydrous tetrahydrofuran under N₂ at -60° C. wasadded n-butyllithium (3.15 mL, 5.0 mmol, 1.6 M solution in hexanes)dropwise via syringe. The resulting mixture was warmed to -20° C. for 10minutes, then cooled back to -60° C.4-(methoxymethyloxy)-phenyldisulfide (800 mg, 2.36 mmol) in 5 mL ofanhydrous tetrahydrofuran was added to the lithio species, and theresultant mixture was allowed to gradually warm to 0° C. After stirringfor 20 minutes, the reaction was quenched by distributing betweenbrine/ethyl acetate (50 mL each). The layers were separated, and theaqueous phase was extracted with ethyl acetate(2×50 mL). The organiclayer was combined, dried (sodium sulfate), and concentrated in vacuo toan oil. Chromatography (silicon dioxide, 5% ethyl acetate/hexanes)provided 287 mg (27%) of[6-methoxy-2-(4-methoxyphenyl)-3-(4-methoxymethyleneoxy)thiophenoxy]benzo[b]thiopheneas a colorless oil. ¹ H NMR (DMSO-d₆) _(d) 7.59 (d, J=8.4 Hz, 2H), 7.58(d, J=2.0 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.03-6.85 (m, 7H), 5.06 (s,2H), 3.79 (s, 3H), 3.76 (s, 3H). FD mass spec: 438. Anal. Calcd. for C₂₄H₂₂ O₄ S₂ : C, 65.73; H, 5.06. Found: C, 65.93; H, 5.10.

EXAMPLE 50 ##STR100##

To a solution of[6-methoxy-2-(4-methoxyphenyl)-3-(4-methoxymethyleneoxy)thiophenoxy]benzo[b]thiophene(233 mg, 0.53 mmol) in 10 mL of a 1:1:2 mixture of methanol:water:tetrahydrofuran was added methane sulfonic acid (0.2 mL, 2.66 mmol). Themixture was heated to reflux for 5 hour. Upon cooling to ambienttemperature, the reaction mixture was diluted with water. The aqueousphase was extracted with ethyl acetate (2×). The organic layer waswashed with sat sodium bicarbonate solution several times. The organiclayer was dried (sodium sulfate) and concentrated in vacuo to provide206 mg (99%) of[6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)thiophenoxy]benzo-[b]thiopheneas a colorless oil. ¹ H NMR (DMSO-d₆) _(d) 9.43 (s, 1H), 7.63 (d, J=8.4Hz, 2H), 7.61 (d, J=2.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.08 (d, J=8.4Hz, 2H), 7.02 (dd, J=8.8, 2.0 Hz, 1H), 6.90 (d, J=8.6 Hz, 2H), 6.63 (d,J=8.6 Hz, 2H). FD mass spec: 395. Anal. Calcd. for C₂₂ H₁₈ O₃ S₂ : C,66.98; H, 4.60. Found: C, 67.26; H, 4.78.

EXAMPLE 51 ##STR101##

To a solution of[6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)thiophenoxy]benzo[b]thiophene(242 mg, 0.61 mmol) in 8.0 mL of anhydrous N,N-dimethylformamide wasadded cesium carbonate (820 mg, 2.5 mmol) followed by2-chloroethylpiperidine hydrochloride (194 mg, 1.05 mmol). The resultingmixture was stirred for 48 hours at ambient temperature and thendistributed between brine/ethyl acetate. The layers were separated, andthe aqueous phase was extracted with ethyl acetate (3×). The organiclayer was dried (sodium sulfate) and concentrated in vacuo to an oil.Chromatography (silicon dioxide, 0-2% methanol/chloroform) provided 244mg (92%) of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo-[b]thiopheneas an amber oil.

EXAMPLE 52

A sample of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenewas converted to its hydrochloride salt according to the standardprocedure in 72% yield ##STR102##

mp 198-201° C. ¹ H NMR (DMSO-d₆) _(d) 7.63 (d, J=8.6 Hz, 2H), 7.62 (d,J=2.0 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.07 (d, J=8.6 Hz, 2H), 7.02 (dd,J=8.2, 2.0 Hz, 1H), 6.92 (q, J_(AB) =9.0 Hz, 4H), 4.24 (bt, 2H), 3.82(s, 3H), 3.80 (s, 3H), 3.49-3.39 (m, 4H), 2.93 (m, 2H), 1.82-1.62 (m,5H), 1.38 (m, 1H). Anal. Calcd. for C₂₉ H₃₂ NO₃ S₂.1.0 HCl: C, 64.28; H,5.95; N, 2.58. Found: C, 64.09; H, 6.08; N, 2.78.

EXAMPLE 53 ##STR103##

To a solution of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride (160 mg, 0.29 mmol) in 15 mL of anhydrous methylenechloride at 0° C. under N₂ was added boron tribromide (0.15 mL). Theresulting dark solution was stirred for 1 hour at 0° C. and thenimmediately poured into a stirred solution of ethyl acetate/sat sodiumbicarbonate solution (50 mL each). The layers were separated, and theaqueous phase was washed with ethyl acetate (3×30 mL). The organic wasdried (sodium sulfate) and concentrated in vacuo to a white solid.Chromatography (silicon dioxide, 0-5% methanol/chloroform) provided 91mg (60%) of[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]-thiopheneas a white solid. mp 123-127° C. ¹ H NMR (DMSO-d₆) _(d) 9.79 (s, 1H),9.71 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.9 Hz, 1H), 7.26 (d,J=2.0 Hz, 1H), 6.91 (d, J=8.8 Hz,2H), 6.82-6.76 (m, 5H), 3.91 (t, J=8.8Hz, 2H), 2.56 (t, J=5.8 Hz, 2H), 2.40 (m, 4H), 1.41-1.28 (m, 6H). FDmass spec: 478. Anal. Calcd. for C₂₇ H₂₇ NO₃ S₂ : C, 67.90; H, 5.70; N,2.93. Found: C, 68.14; H, 5.84; N, 2.65.

EXAMPLE 54 ##STR104##

mp 180-190° C. ¹ H NMR (DMSO-d₆) _(d) 9.86 (s, 1H), 9.79 (s, 1H), 7.46(d, J=8.5 Hz, 2H), 7.42 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 6.96(d, J=8.7 Hz, 2H), 6.86-6.81 (m, 5H), 4.27 (m, 2H), 3.41-3.37 (m, 4H),2.96-2.84 (m, 2H), 1.77-1.60 (m, 5H), 1.35-1.28 (m, 1H). FD mass spec:477. Anal. Calcd. for C₂₇ H₂₇ NO₃ S₂.2.2 HCl: C, 58.13; H, 5.28; N,2.51. Found: C, 58.11; H, 5.10; N, 2.61.

Prepared by the same procedures were:

EXAMPLE 55 ##STR105##

mp 215-218° C. ¹ H NMR (DMSO-d₆) _(d) 7.61-7.58 (m, 3H) 7.52 (d, J=8.8Hz, 1H), 7.04-6.95 (m, 5H), 6.86 (d, J=8.8 Hz, 2H), 4.22 (bt, 2H), 3.79(s, 3H), 3.76 (s, 3H), 3.47-3.42 (m, 4H), 3.01 (m, 2H), 1.94-1.80 (m,4H). FD mass spec: 491. Anal. Calcd. for C₂₈ H₂₉ NO₃ S₂.1.0HCl: C,63.67; H, 5.73; N, 2.65. Found: C, 63.47; H, 5.78; N, 2.65.

EXAMPLE 56 ##STR106##

mp 137-140° C. (dec). ¹ H NMR (DMSO-d₆) _(d) 9.86 (s, 1H), 9.80 (s, 1H),7.46 (d, J=8.6 Hz, 2H), 7.42 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H),6.96 (d, J=8.7 Hz, 2H), 6.87-6.81 (m, 5H), 4.21 (bt, 2H), 3.53-3.41 (m,4H), 3.01 (m, 2H), 1.95-1.82 (m, 4H). FD mass spec: 464. Anal. Calcd.for C₂₆ H₂₅ NO₃ S₂.1.0HCl: C, 62.45; H, 5.24; N, 2.80. Found: C, 62.36;H, 5.37; N, 2.61.

EXAMPLE 57

Prepared from the product of Example 45 by the hydrogenolysis of thetriflate as described below in Example 58 was6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(phenyl)]benzo[b]thiophenehydrochloride ##STR107##

mp 187-195° C. ¹ H NMR (DMSO-d₆) _(d) 7.66 (d, J=2.8 Hz, 2H), 7.58 (d,J=2.0 Hz, 1H), 7.39 (t, J=7.5 Hz, 2H), 7.28 (m, 1H), 7.17 (d, J=8.8 Hz,1H), 6.91 (dd, J=8.8, 2.0 Hz, 1H), 6.89 (s, 4H), 4.23 (bt, J=5.7 Hz,2H), 3.79 (s, 3H), 3.45-3.38 (m, 4H), 2.98 (m, 2H), 1.77-1.61 (m, 5H),1.31 (m, 1H). FD mass spec: 460. Anal. Calcd. for C₂₈ H₂₉ NO₃ S.1.0HCl:C, 67.80; H, 6.10; N, 2.84. Found: C, 67.62; H, 5.89; N, 2.67.

EXAMPLE 58 ##STR108##

To a solution of6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophenehydrochloride (5.00 g, 10.0 mmol) in 100 mL of anhydrous methylenechloride at 0° C. under N₂ was added triethylamine (8.38 mL, 60.0 mmol)followed by triflouromethanesulfonic anhydride (1.69 mL, 10.0 mmol). Theresulting mixture was allowed to gradually warm to room temperature andstirred for 1.5 hours. The reaction was then quenched by pouring into200 mL of saturated sodium bicarbonate solution. The aqueous phase wasthen extracted with ethyl acetate (3.x 100 mL). The organic layer wasdried (sodium sulfate) and concentrated in vacuo to an oil.Chromatography (0-3% methanol/chloroform) provided 2.82 g (39%) of6-triflouromethanesulfonate-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-triflouromethane-sulfonatephenyl)]benzo[b]thiophene,1.82 g (31%) of a 1:1 mixture of 6-triflouromethanesulfonate-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-phenyl)]benzo[b]thiopheneand3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-triflouromethanesulfonatephenyl)]benzo[b]thiophene,and 1.48 g (36%) of recovered staring material as the free base.

To a solution of a 1:1 mixture of monotriflate derivatives from the lastreaction (0.50 g, 0.84 mmol) in 60 mL of ethanol-ethyl acetate (5:1) wasadded triethylamine (2.0 mL) and 5% palladium-on-carbon (0.50 g). Theresulting mixture was hydrogenated at 40 psi for 2 hours. The mixturewas then filtered through Celite® to remove the catalyst. The filtratewas concentrated to an oil. The resulting mixture of monohydroxyderivatives was dissolved in ethyl acetate from which3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]-thiopheneprecipitated. The filtrate consisted of a 4:1 mixture of monohydroxyderivatives where6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(phenyl)]benzo[b]thiophenewas the major component. The filtrate was concentrated in vacuo, and theresulting solid dissolved in minimal ethyl acetate and treated withethyl ether-hydrochloric acid. The resulting solid was recrystallizedfrom ethanol to give 69 mg (18%) of isomerically pure6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(phenyl)]benzo[b]thiophenehydrochloride. mp 217-219° C. ¹ H NMR (DMSO-d₆) _(d) 9.87 (s, 1H), 7.64(d, J=7.5 Hz, 2H), 7.39-7.26 (m, 4H), 7.10 (d, J=8.6 Hz, 1H), 6.89 (s,4H), 6.78 (dd, J=8.6, 2.0 Hz, 1H), 4.22 (bt, 2H), 3.39-3.37 (m, 4H),2.97-2.90 (m, 2H), 1.74-1.60 (m, 5H), 1.39 (m, 1H). FD mass spec: 446.Anal. Calcd. for C₂₇ H₂₇ NO₃ S.1.0HCl: C, 67.28; H, 5.86; N, 2.91.Found: C, 67.00; H, 5.59; N, 2.87. Alternatively, Example 58 is preparedby demethylation of the product of Example 57 as described in Example18.

EXAMPLE 59 ##STR109##

Yellow oil. ¹ H NMR (DMSO-d₆) _(d) 7.69 (d, J=2.0 Hz, 1H), 7.67(d, J=8.6Hz, 2H), 7.09-6.99 (m, 5H), 6.96-6.87 (m, 3H), 4.76 (septet, J=6.0 Hz,1H), 3.99 (bt, J=6.0 Hz, 2H), 3.78 (s, 3H), 2.61 (bt, J=6.0 Hz, 2H),2.44-2.37 (m, 4H), 1.53-1.43 (m, 4H), 1.40-1.32 (m, 2H), 1.29 (d, J=6.0Hz, 6H). FD mass spec 533. Anal. Calcd. for C₃₅ H₃₅ NO₅ S.0.67 H₂ O: C,68.23; H, 6.71; N, 2.57. Found: C, 67.90; H, 6.31; N, 2.53. ##STR110##

mp 168-170° C. ¹ H NMR (DMSO-d₆) _(d) 10.37 (s, 1H), 7.58 (d, J=8.6 Hz,2H), 7.52 (d, J=1.3 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 6.95 (d, J=8.6 Hz,2H), 6.92-6.85 (m, 5H), 4.64 (septet, J=6.0 Hz, 1H), 4.28 (bt, J=6.0 Hz,2H), 3.72 (s, 3H), 3.44-3.37 (m, 4H), 2.95-2.89 (m, 2H), 1.73-1.60 (m,5H), 1.36-1.28 (m, 1H), 1.25 (d, J=6.0 Hz, 6H). FD mass spec 517. Anal.Calcd. for C₃ H₃₅ NO₄ S.HCl: C, 67.19; H, 6.55; N, 2.53. Found: C,67.15; H, 6.29; N, 2.62.

[6-Isopropoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophenehydrochloride was converted to[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiopheneby treatment with 2.0 equivalents of BCl₃ at 0-10 ° C. in anhydrousdichloromethane (the methyl ether is not cleaved under theseconditions).

Test Procedure General Preparation Procedure

In the examples illustrating the methods, a post-menopausal model wasused in which effects of different treatments upon circulating lipidswere determined.

Seventy-five day old female Sprague Dawley rats (weight range of 200 to225 g) were obtained from Charles River Laboratories (Portage, Mich.).The animals were either bilaterally ovariectomized (OVX) or exposed to aSham surgical procedure at Charles River Laboratories, and then shippedafter one week. Upon arrival, they were housed in metal hanging cages ingroups of 3 or 4 per cage and had ad libitum access to food (calciumcontent approximately 0.5%) and water for one week. Room temperature wasmaintained at 22.2°±1.7° C. with a minimum relative humidity of 40%. Thephotoperiod in the room was 12 hours light and 12 hours dark.

Dosing Regimen Tissue Collection

After a one week acclimation period (therefore, two weeks post--OVX)daily dosing with test compound was initiated. 17a-ethynyl estradiol orthe test compound were given orally, unless otherwise stated, as asuspension in 1% carboxymethylcellulose or dissolved in 20%cyclodextrin. Animals were dosed daily for 4 days. Following the dosingregimen, animals were weighed and anesthetized with a ketamine: Xylazine(2:1, V:V) mixture and a blood sample was collected by cardiac puncture.The animals were then sacrificed by asphyxiation with CO₂, the uteruswas removed through a midline incision, and a wet uterine weight wasdetermined.

Cholesterol Analysis

Blood samples were allowed to clot at room temperature for 2 hours, andserum was obtained following centrifugation for 10 minutes at 3000 rpm.Serum cholesterol was determined using a Boehringer Mannheim Diagnosticshigh performance cholesterol assay. Briefly the cholesterol was oxidizedto cholest-4-en-3-one and hydrogen peroxide. The hydrogen peroxide wasthen reacted with phenol and 4-aminophenazone in the presence ofperoxidase to produce a p-quinone imine dye, which was readspectrophotemetrically at 500 nm. Cholesterol concentration was thencalculated against a standard curve. The entire assay was automatedusing a Biomek Automated Workstation.

Uterine Eosinophil Peroxidase (EPO) Assay

Uteri were kept at 4° C. until time of enzymatic analysis. The uteriwere then homogenized in 50 volumes of 50 mM Tris buffer (pH-8.0)containing 0.005% Triton X-100. Upon addition of 0.01% hydrogen peroxideand 10 mM O-phenylenediamine (final concentrations) in Tris buffer,increase in absorbance was monitored for one minute at 450 nm. Thepresence of eosonophils in the uterus is an indication of estrogenicactivity of a compound. The maximal velocity of a 15 second interval wasdetermined over the initial, linear portion of the reaction curve.

Source of Compound

17a-ethynyl estradiol was obtained from Sigma Chemical Co., St. Louis,Mo.

Influence of Formula I Compounds on Serum Cholesterol and Determinationof Agonist/Non-Agonist Activity

Data presented in Table 1 below show comparative results amongovariectomized rats, rats treated with 17a-ethynyl estradiol (EE₂ ; anorally available form of estrogen), and rats treated with certaincompounds of the present invention. Although EE₂ caused a decrease inserum cholesterol when orally administered at 0.1 mg/kg/day, it alsoexerted a stimulatory action on the uterus so that EE₂ uterine weightwas substantially greater than the uterine weight of ovariectomized testanimals. This uterine response to estrogen is well recognized in theart.

Not only did the compounds of the present invention generally reduceserum cholesterol compared to the ovariectomized control animals, bututerine weight was only minimally increased to slightly decreased withthe majority of the formula compounds tested. Compared to estrogeniccompounds known in the art, the benefit of serum cholesterol reductionwithout adversely affecting uterine weight is quite rare and desirable.

As is expressed in the below data, estrogenicity also was assessed byevaluating the adverse response of eosinophil infiltration into theuterus. The compounds of the present invention did not cause anyincrease in the number of eosinophils observed in the stromal layer ofovariectomized rats, while estradiol cause a substantial, expectedincrease in eosinophil infiltration.

The data presented in the Tables 1 below reflects the response of 5 to 6rats per treatment.

                  TABLE 1                                                         ______________________________________                                                        Uterine Weight                                                                           Uterine                                                                              Serum Cholesterol                                   Dose    (% increase                                                                              EPO    (% decrease                                 Compound                                                                              mg/kg   vs. OVX)   (V. max)                                                                             vs. OVX)                                    ______________________________________                                        EE.sub.2                                                                              0.1     229.2      308.1  94.8                                        Example 3                                                                             0.01    29.1       1.8    50.6                                                0.1     55.4       4.8    47.8                                                1.0     61.9       5.4    49.2                                        Example 4                                                                             0.1     33.2       3.9    53.7                                                1.0     35.6       4.8    62.1                                                10.0    34.7       3.0    65.3                                        Example 5                                                                             0.1     66.7       7.2    67.2                                                1.0     106.9      54.6   67.7                                                10.0    109.8      59.4   60.2                                        Example 7                                                                             0.1     32.0       4.8    56.2                                                1.0     44.3       4.5    42.6                                                5.0     41.6       4.8    29.5                                        Example 10                                                                            0.1     19.7       12.0   50.2                                                1.0     18.4       17.7   59.0                                                10.0    13.3       4.8    38.9                                        Example 19                                                                            0.01    11.4       2.1    25.1                                                0.1     24.9       2.4    45.3                                                1.0     24.7       3.6    53.6                                        Example 20                                                                            0.01    16.9       0.9    29.4                                                0.05    40.9       3.0    35.9                                                0.1     30.6       3.0    58.7                                        Example 21                                                                            0.01    21.0       1.2    26.8                                                0.1     24.8       4.8    47.5                                                1.0     51.4       9.3    54.4                                        Example 23                                                                            0.01    21.6       3.3    36.2                                                0.1     33.4       84.3   47.2                                                1.0     148.9      150.6  66.1                                        Example 24                                                                            0.01    9.2        3.6    23.7                                                0.1     18.2       0.9    46.4                                                1.0     81.0       29.4   79.3                                        Example 25                                                                            0.01    5.4        3.0    13.1                                                0.1     16.7       3.3    67.6                                                1.0     96.6       36.0   73.9                                        Example 26                                                                            0.01    14.0       4.8    29.0                                                0.1     81.0       29.1   45.2                                                1.0     117.1      175.1  62.7                                        Example 27                                                                            0.01    2.2        3.3    12.2                                                0.1     49.2       4.8    50.8                                                1.0     86.4       52.5   76.5                                        Example 43                                                                            0.01    0.0        3.3    9.2                                                 0.1     17.2       4.8    43.8                                                1.0     31.0       6.0    39.4                                        Example 44                                                                            0.01    43.8       3.6    12.6                                                0.1     80.5       88.5   43.8                                                1.0     74.8       94.5   67.4                                        Example 53                                                                            0.1     40.6       0.9    62.7                                                1.0     24.1       1.3    57.5                                                10.0    32.0       4.8    58.7                                        ______________________________________                                    

In addition to the demonstrated benefits of the compounds of the presentinvention, especially when compared to estradiol, the above data clearlydemonstrate that compounds of Formula I are not estrogen mimetics.Furthermore, no deleterious toxicological effects (survival) wereobserved with any treatment.

Osteoporosis Test Procedure

Following the General Preparation Procedure, infra, the rats weretreated daily for 35 days (6 rats per treatment group) and sacrificed bycarbon dioxide asphyxiation on the 36th day. The 35 day time period wassufficient to allow maximal reduction in bone density, measured asdescribed herein. At the time of sacrifice, the uteri were removed,dissected free of extraneous tissue, and the fluid contents wereexpelled before determination of wet weight in order to confirm estrogendeficiency associated with complete ovariectomy. Uterine weight wasroutinely reduced about 75% in response to ovariectomy. The uteri werethen placed in 10% neutral buffered formalin to allow for subsequenthistological analysis.

The right femurs were excised and digitilized x-rays generated andanalyzed by an image analysis program (NIH image) at the distalmetaphysis. The proximal aspect of the tibiae from these animals werealso scanned by quantitative computed tomography.

In accordance with the above procedures, compounds of the presentinvention and ethynyl estradiol (EE₂) in 20% hydroxypropylb-cyclodextrin were orally administered to test animals. Distal femurmetaphysis data presented in Tables 2 and 3 below are the results offormula I compound treatments compared to intact and ovariectomized testanimals. Results are reported as the mean ± the standard error of themean.

                  TABLE 2                                                         ______________________________________                                                                Distal Femur Metaphysis                                                       (X-ray Image Analysis-                                Compound/Treatment                                                                          Dose/kg   Gray Score)                                           ______________________________________                                        Sham (20% cyclodextrin)                                                                     --        27.2 ± 6.0                                         Overiectomy control                                                                         --        8.1 ± 1.8                                          (20% cyclodextrin)                                                            EE2           0.1 mg    11.5 ± 2.9*                                        Example 19    0.1 mg    14.7 ± 1.9                                                       1.0 mg    15.0 ± 3.5*                                                      10.0 mg   15.3 ± 4.0*                                        ______________________________________                                         *P <= 0.5 two tailed Student's T Test on raw data.                       

                  TABLE 3                                                         ______________________________________                                                                Distal Femur Metaphysis                                                       (X-ray Image Analysis-                                Compound/Treatment                                                                          Dose/kg   Gray Score)                                           ______________________________________                                        Sham (20% cyclodextrin)                                                                     --        31.1 ± 6.3                                         Overiectomy control                                                                         --        6.2 ± 1.4                                          (20% cyclodextrin)                                                            EE2           0.1 mg    17.8 ± 3.5                                         Example 10    0.1 mg    15.3 ± 3.0                                                       1.0 mg    15.2 ± 3.7                                                       3.0 mg    18.5 ± 3.2*                                        Example 24    0.1 mg    18.3 ± 2.6*                                                      1.0 mg    19.6 ± 2.3*                                                      3.0 mg    17.1 ± 5.5                                         ______________________________________                                         *P <= 0.05 two tailed Student's T Test on raw data.                      

In summary, ovariectomy of the test animals caused a significantreduction in femur density compared to intact, vehicle treated controls.Orally administered ethynyl estradiol (EE₂) prevented this loss, but therisk of uterine stimulation with this treatment is ever-present.

The compounds of the present invention also prevented bone loss in ageneral, dose-dependent manner. Accordingly, the compounds of thepresent invention are useful for the treatment of post-menopausalsyndrome, particularly osteoporosis.

MCF-7 Proliferation Assay

MCF-7 breast adenocarcinoma cells (ATCC HTB 22) were maintained in MEM(minimal essential medium, phenol red-free, Sigma, St. Louis, Mo.)supplimented with 10% fetal bovine serum (FBS) (V/V), L-glutamine (2mM), sodium pyruvate (1 mM), HEPES{(N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]10 mM},non-essential amino acids and bovine insulin (1 ug/mL) (maintenancemedium). Ten days prior to assay, MCF-7 cells were switched tomaintenance medium supplemented with 10% dextran coated charcoalstripped fetal bovine serum (DCC-FBS) assay medium) in place of 10% FBSto deplete internal stores of steroids. MCF-7 cells were removed frommaintenance flasks using cell dissociation medium (Ca++/Mg++ free HBSS(phenol red-free) supplemented with 10 mM HEPES and 2 mM EDTA). Cellswere washed twice with assay medium and adjusted to 80,000 cells/mL.Approximately 100 mL (8,000 cells) were added to flat-bottommicroculture wells (Costar 3596) and incubated at 37° C. in a 5% CO₂humidified incubator for 48 hours to allow for cell adherence andequilibration after transfer. Serial dilutions of drugs or DMSO as adiluent control were prepared in assay medium and 50 mL transferred totriplicate microcultures followed by 50 mL assay medium for a finalvolume of 200 mL. After an additional 48 hours at 37° C. in a 5% CO₂humidified incubator, microcultures were pulsed with tritiated thymidine(1 uCi/well) for 4 hours. Cultures were terminated by freezing at -70°C. for 24 hours followed by thawing and harvesting of microculturesusing a Skatron Semiautomatic Cell Harvester. Samples were counted byliquid scintillation using a Wallac BetaPlace b counter. Results inTable 4 below show the IC₅₀ for certain compounds of the presentinvention.

                  TABLE 4                                                         ______________________________________                                               Compound                                                                              IC.sub.50 nM                                                   ______________________________________                                               Example 3                                                                             4.0                                                                   Example 10                                                                            2.00                                                                  Example 19                                                                            0.028                                                                 Example 21                                                                            0.05                                                                  Example 23                                                                            0.08                                                                  Example 53                                                                            0.28                                                           ______________________________________                                    

DMBA-Induced Mammary Tumor Inhibition

Estrogen-dependent mammary tumors are produced in female Sprague-Dawleyrats which are purchased from Harlan Industries, Indianapolis, Ind. Atabout 55 days of age, the rats receive a single oral feeding of 20 mg of7,12-dimethylbenz[a]anthracene (DMBA). About 6 weeks after DMBAadministration, the mammary glands are palpated at weekly intervals forthe appearance of tumors. Whenever one or more tumors appear, thelongest and shortest diameters of each tumor are measured with a metriccaliper, the measurements are recorded, and that animal is selected forexperimentation. An attempt is made to uniformly distribute the varioussizes of tumors in the treated and control groups such thataverage-sized tumors are equivalently distributed between test groups.Control groups and test groups for each experiment contain 5 to 9animals.

Compounds of Formula I are administered either through intraperitonealinjections in 2% acacia, or orally. Orally administered compounds areeither dissolved or suspended in 0.2 mL corn oil. Each treatment,including acacia and corn oil control treatments, is administered oncedaily to each test animal. Following the initial tumor measurement andselection of test animals, tumors are measured each week by theabove-mentioned method. The treatment and measurements of animalscontinue for 3 to 5 weeks at which time the final areas of the tumorsare determined. For each compound and control treatment, the change inthe mean tumor area is determined.

Uterine Fibrosis Test Procedures

Test 1

Between 3 and 20 women having uterine fibrosis are administered acompound of the present invention. The amount of compound administeredis from 0.1 to 1000 mg/day, and the period of administration is 3months.

The women are observed during the period of administration, and up to 3months after discontinuance of administration, for effects on uterinefibrosis.

Test 2

The same procedure is used as in Test 1, except the period ofadministration is 6 months.

Test 3

The same procedure is used as in Test 1, except the period ofadministration is 1 year.

Test 4

A. Induction of fibroid tumors in guinea pig

Prolonged estrogen stimulation is used to induce leiomyomata in sexuallymature female guinea pigs. Animals are dosed with estradiol 3-5 timesper week by injection for 2-4 months or until tumors arise. Treatmentsconsisting of a compound of the invention or vehicle is administereddaily for 3-16 weeks and then animals are sacrificed and the uteriharvested and analyzed for tumor regression.

B. Implantation of human uterine fibroid tissue in nude mice

Tissue from human leiomyomas are implanted into the peritoneal cavityand or uterine myometrium of sexually mature, castrated, female, nudemice. Exogenous estrogen are supplied to induce growth of the explantedtissue. In some cases, the harvested tumor cells are cultured in vitroprior to implantation. Treatment consisting of a compound of the presentinvention or vehicle is supplied by gastric lavage on a daily basis for3-16 weeks and implants are removed and measured for growth orregression. At the time of sacrifice, the uteri is harvested to assessthe status of the organ.

Test 5

A. Tissue from human uterine fibroid tumors is harvested and maintained,in vitro, as primary nontransformed cultures. Surgical specimens arepushed through a sterile mesh or sieve, or alternately teased apart fromsurrounding tissue to produce a single cell suspension. Cells aremaintained in media containing 10% serum and antibiotic. Rates of growthin the presence and absence of estrogen are determined. Cells areassayed for their ability to produce complement component C3 and theirresponse to growth factors and growth hormone. In vitro cultures areassessed for their proliferative response following treatment withprogestins, GnRH, a compound of the present invention and vehicle.Levels of steroid hormone receptors are assessed weekly to determinewhether important cell characteristics are maintained in vitro. Tissuefrom 5-25 patients are utilized.

Activity in at least one of the above tests indicates the compounds ofthe present invention are of potential in the treatment of uterinefibrosis.

Endometriosis Test Procedure

In Tests 1 and 2, effects of 14-day and 21-day administration ofcompounds of the present invention on the growth of explantedendometrial tissue can be examined.

Test 1

Twelve to thirty adult CD strain female rats are used as test animals.They are divided into three groups of equal numbers. The estrous cycleof all animals is monitored. On the day of proestrus, surgery isperformed on each female. Females in each group have the left uterinehorn removed, sectioned into small squares, and the squares are looselysutured at various sites adjacent to the mesenteric blood flow. Inaddition, females in Group 2 have the ovaries removed.

On the day following surgery, animals in Groups 1 and 2 receiveintraperitoneal injections of water for 14 days whereas animals in Group3 receive intraperitoneal injections of 1.0 mg of a compound of thepresent invention per kilogram of body weight for the same duration.Following 14 days of treatment, each female is sacrificed and theendometrial explants, adrenals, remaining uterus, and ovaries, whereapplicable, are removed and prepared for histological examination. Theovaries and adrenals are weighed.

Test 2

Twelve to thirty adult CD strain female rats are used as test animals.They are divided into two equal groups. The estrous cycle of all animalsis monitored. On the day of proestrus, surgery is performed on eachfemale. Females in each group have the left uterine horn removed,sectioned into small squares, and the squares are loosely sutured atvarious sites adjacent to the mesenteric blood flow.

Approximately 50 days following surgery, animals assigned to Group 1receive intraperitoneal injections of water for 21 days whereas animalsin Group 2 receive intraperitoneal injections of 1.0 mg of a compound ofthe present invention per kilogram of body weight for the same duration.Following 21 days of treatment, each female is sacrificed and theendometrial explants and adrenals are removed and weighed. The explantsare measured as an indication of growth. Estrous cycles are monitored.

Test 3

A. Surgical induction of endometriosis

Autographs of endometrial tissue are used to induce endometriosis inrats and/or rabbits. Female animals at reproductive maturity undergobilateral oophorectomy, and estrogen is supplied exogenously thusproviding a specific and constant level of hormone. Autologousendometrial tissue is implanted in the peritoneum of 5-150 animals andestrogen supplied to induce growth of the explanted tissue. Treatmentconsisting of a compound of the present invention is supplied by gastriclavage on a daily basis for 3-16 weeks, and implants are removed andmeasured for growth or regression. At the time of sacrifice, the intacthorn of the uterus is harvested to assess status of endometrium.

B. Implantation of human endometrial tissue in nude mice

Tissue from human endometrial lesions is implanted into the peritoneumof sexually mature, castrated, female, nude mice. Exogenous estrogen issupplied to induce growth of the explanted tissue. In some cases, theharvested endometrial cells are cultured in vitro prior to implantation.Treatment consisting of a compound of the present invention supplied bygastric lavage on a daily basis for 3-16 weeks, and implants are removedand measured for growth or regression. At the time of sacrifice, theuteri is harvested to assess the status of the intact endometrium.

Test 4

A. Tissue from human endometrial lesions is harvested and maintained invitro as primary nontransformed cultures. Surgical specimens are pushedthrough a sterile mesh or sieve, or alternately teased apart fromsurrounding tissue to produce a single cell suspension. Cells aremaintained in media containing 10% serum and antibiotic. Rates of growthin the presence and absence of estrogen are determined. Cells areassayed for their ability to produce complement component C3 and theirresponse to growth factors and growth hormone. In vitro cultures areassessed for their proliferative response following treatment withprogestins, GnRH, a compound of the invention, and vehicle. Levels ofsteroid hormone receptors are assessed weekly to determine whetherimportant cell characteristics are maintained in vitro. Tissue from 5-25patients is utilized.

Activity in any of the above assays indicates that the compounds of thepresent invention are useful in the treatment of endometriosis.

The present invention also provides a method of alleviatingpost-menopausal syndrome in women which comprises the aforementionedmethod using compounds of Formula I and further comprises administeringto a woman an effective amount of estrogen or progestin. Thesetreatments are particularly useful for treating osteoporosis andlowering serum cholesterol because the patient will receive the benefitsof each pharmaceutical agent while the compounds of the presentinvention would inhibit undesirable side-effects of estrogen andprogestin. Activity of these combination treatments in any of thepost-menopausal tests, infra, indicates that the combination treatmentsare useful for alleviating the symptoms of post-menopausal symptoms inwomen.

Various forms of estrogen and progestin are commercially available.Estrogen-based agents include, for example, ethynyl estrogen (0.01-0.03mg/day), mestranol (0.05-0.15 mg/day), and conjugated estrogenichormones such as Premarin® (Wyeth-Ayerst; 0.3-2.5 mg/day).Progestin-based agents include, for example, medroxyprogesterone such asProvera® (Upjohn; 2.5-10 mg/day), norethylnodrel (1.0-10.0 mg/day), andnonethindrone (0.5-2.0 mg/day). A preferred estrogen-based compound isPremarin, and norethylnodrel and norethindrone are preferredprogestin-based agents.

The method of administration of each estrogen- and progestin-based agentis consistent with that which is known in the art. For the majority ofthe methods of the present invention, compounds of Formula I areadministered continuously, from 1 to 3 times daily. However, cyclicaltherapy may especially be useful in the treatment of endometriosis ormay be used acutely during painful attacks of the disease. In the caseof restenosis, therapy may be limited to short (1-6 months) intervalsfollowing medical procedures such as angioplasty.

As used herein, the term "effective amount" means an amount of compoundof the present invention which is capable of alleviating the symptoms ofthe various pathological conditions herein described. The specific doseof a compound administered according to this invention will, of course,be determined by the particular circumstances surrounding the caseincluding, for example, the compound administered, the route ofadministration, the state of being of the patient, and the pathologicalcondition being treated. A typical daily dose will contain a nontoxicdosage level of from about 5 mg to about 600 mg/day of a compound of thepresent invention. Preferred daily doses generally will be from about 15mg to about 80 mg/day.

The compounds of this invention can be administered by a variety ofroutes including oral, rectal, transdermal, subcutaneous, intravenous,intramuscular, and intranasal. These compounds preferably are formulatedprior to administration, the selection of which will be decided by theattending physician. Thus, another aspect of the present invention is apharmaceutical composition comprising an effective amount of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, optionallycontaining an effective amount of estrogen or progestin, and apharmaceutically acceptable carrier, diluent, or excipient.

The total active ingredients in such formulations comprises from 0.1% to99.9% by weight of the formulation. By "pharmaceutically acceptable" itis meant the carrier, diluent, excipients and salt must be compatiblewith the other ingredients of the formulation, and not deleterious tothe recipient thereof.

Pharmaceutical formulations of the present invention can be prepared byprocedures known in the art using well known and readily availableingredients. For example, the compounds of formula I, with or without anestrogen or progestin compound, can be formulated with commonexcipients, diluents, or carriers, and formed into tablets, capsules,suspensions, powders, and the like. Examples of excipients, diluents,and carriers that are suitable for such formulations include thefollowing: fillers and extenders such as starch, sugars, mannitol, andsilicic derivatives; binding agents such as carboxymethyl cellulose andother cellulose derivatives, alginates, gelatin, andpolyvinylpyrrolidone; moisturizing agents such as glycerol;disintegrating agents such as calcium carbonate and sodium bicarbonate;agents for retarding dissolution such as paraffin; resorptionaccelerators such as quaternary ammonium compounds; surface activeagents such as cetyl alcohol, glycerol monostearate; adsorptive carrierssuch as kaolin and bentonite; and lubricants such as talc, calcium andmagnesium stearate, and solid polyethyl glycols.

The compounds also can be formulated as elixirs or solutions forconvenient oral administration or as solutions appropriate forparenteral administration, for example, by intramuscular, subcutaneousor intravenous routes. Additionally, the compounds are well suited toformulation as sustained release dosage forms and the like. Theformulations can be so constituted that they release the activeingredient only or preferably in a particular physiological location,possibly over a period of time. The coatings, envelopes, and protectivematrices may be made, for example, from polymeric substances or waxes.

Compounds of formula I, alone or in combination with a pharmaceuticalagent of the present invention, generally will be administered in aconvenient formulation. The following formulation examples only areillustrative and are not intended to limit the scope of the presentinvention.

Formulations

In the formulations which follow, "active ingredient" means a compoundof formula I, or a salt or solvate thereof.

Formulation 1: Gelatin Capsules

    ______________________________________                                        Hard gelatin capsules are                                                     prepared using the                                                            Ingredient        Quantity (mg/capsule)                                       ______________________________________                                        Active ingredient 0.1-1000                                                    Starch, NF        0-650                                                       Starch flowable powder                                                                          0-650                                                       Silicone fluid 350 centistokes                                                                  0-15                                                        ______________________________________                                    

The formulation above may be changed in compliance with the reasonablevariations provided.

A tablet formulation is prepared using the ingredients below:

Formulation 2: Tablets

    ______________________________________                                        Ingredient       Quantity (mg/tablet)                                         ______________________________________                                        Active ingredient                                                                               2.5-1000                                                    Cellulose, microcrystalline                                                                    200-650                                                      Silicon dioxide, fumed                                                                         10-650                                                       Stearate acid    5-15                                                         ______________________________________                                    

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 2.5-1000 mg of active ingredientare made up as follows:

Formulation 3: Tablets

    ______________________________________                                        Ingredient         Quantity (mg/tablet)                                       ______________________________________                                        Active ingredient  25-1000                                                    Starch             45                                                         Cellulose, microcrystalline                                                                      35                                                         Polyvinylpyrrolidone                                                                             4                                                          (as 10% solution in water)                                                    Sodium carboxymethyl cellulose                                                                   4.5                                                        Magnesium stearate 0.5                                                        Talc               1                                                          ______________________________________                                    

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve mixed thoroughly. The solution of polyvinylpyrrolidoneis mixed with the resultant powders which are then passed through a No.14 mesh U.S. sieve. The granules so produced are dried at 50°-60° C. andpassed through a No. 18 mesh U.S. sieve. The sodium carboxymethylstarch, magnesium stearate, and talc, previously passed through a No. 60U.S. sieve, are then added to the granules which, after mixing, arecompressed on a tablet machine to yield tablets.

Suspensions each containing 0.1-1000 mg of medicament per 5 ml dose aremade as follows:

Formulation 4: Suspensions

    ______________________________________                                        Ingredient           Quantity (mg/5 ml)                                       ______________________________________                                        Active ingredient    0.1-1000  mg                                             Sodium carboxymethyl cellulose                                                                     50        mg                                             Syrup                1.25      mg                                             Benzoic acid solution                                                                              0.10      mL                                             Flavor               q.v.                                                     Color                q.v.                                                     Purified water to    5         mL                                             ______________________________________                                    

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethyl cellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor, and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume.

An aerosol solution is prepared containing the following ingredients:

Formulation 5: Aerosol

    ______________________________________                                        Ingredient          Quantity (% by weight)                                    ______________________________________                                        Active ingredient   0.25                                                      Ethanol             25.75                                                     Propellant 22 (Chlorodifluoromethane)                                                             70.00                                                     ______________________________________                                    

The active ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C., and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remaining propellant. The valve units arethen fitted to the container.

Suppositories are prepared as follows:

Formulation 6: Suppositories

    ______________________________________                                        Ingredient       Quantity (mg/suppository)                                    ______________________________________                                        Active ingredient                                                                              250                                                          Saturated fatty acid glycerides                                                                2,000                                                        ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimal necessary heat. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

An intravenous formulation is prepared as follows:

Formulation 7: Intravenous Solution

    ______________________________________                                        Ingredient            Quantity                                                ______________________________________                                        Active ingredient     50     mg                                               Isotonic saline       1,000  mL                                               ______________________________________                                    

The solution of the above ingredients is intravenously administered to apatient at a rate of about 1 mL per minute.

Formulation 8: Combination Capsule I

    ______________________________________                                        Ingredient    Quantity (mg/capsule)                                           ______________________________________                                        Active ingredient                                                                           50                                                              Premarin      1                                                               Avicel pH 101 50                                                              Starch 1500   117.50                                                          Silicon Oil   2                                                               Tween 80      0.50                                                            Cab-O-Sil     0.25                                                            ______________________________________                                    

Formulation 9: Combination Capsule II

    ______________________________________                                        Ingredient    Quantity (mg/capsule)                                           ______________________________________                                        Active ingredient                                                                           50                                                              Norethylnodrel                                                                              5                                                               Avicel pH 101 82.50                                                           Starch 1500   90                                                              Silicon Oil   2                                                               Tween 80      0.50                                                            ______________________________________                                    

Formulation 10: Combination Tablet

    ______________________________________                                        Ingredient     Quantity (mg/capsule)                                          ______________________________________                                        Active ingredient                                                                            50                                                             Premarin       1                                                              Corn Starch NF 50                                                             Povidone, K29-32                                                                             6                                                              Avicel pH 101  41.50                                                          Avicel pH 102  136.50                                                         Crospovidone XL10                                                                            2.50                                                           Magnesium Stearate                                                                           0.50                                                           Cab-O-Sil      0.50                                                           ______________________________________                                    

I claim:
 1. A method for inhibiting hyperlipidemia resulted fromestrogen deficiency disease comprising administering to a patient inneed of treatment an effective amount of a compound of formula I##STR111## wherein R¹ is --H, --OH, --O(C₁ -C₄ alkyl), --OCOC₆ H₅,--OCO(C₁ -C₆ alkyl), or --OSO₂ (C₂ -C₆ alkyl);R² is --H, --OH, --O(C₁-C₄ alkyl), --OCOC₆ H₅, --OCO(C₁ -C₆ alkyl), --OSO₂ (C₂ -C₆ alkyl) orhalo; R³ is 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl,dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino,diisopropylamino, or 1-hexamethyleneimino; n is 2 or 3; and Z is --O--or --S--;or a pharmaceutically acceptable salt thereof.
 2. A methodaccording to claim 1 wherein Z is --O--, n is 2, and R³ is1-piperidinyl, or a pharmaceutically acceptable salt thereof.
 3. Amethod according to claim 2 wherein R¹ and R² each are --O(C₁ -C₄alkyl), or a pharmaceutically acceptable salt thereof.
 4. A methodaccording to claim 3 wherein R¹ and R² each are --OCH₃, or apharmaceutically acceptable salt thereof.
 5. A method according to claim4 wherein said salt thereof is the hydrochloride salt.
 6. A methodaccording to claim 2 wherein R¹ is --OH and R² is --O(C₁ -C₄ alkyl), ora pharmaceutically acceptable salt thereof.
 7. A method for inhibitinghyperlipidema resulted from estrogen deficiency comprising administeringto a patient in need of treatment an effective amount of a compound ofthe formula ##STR112## or a pharmaceutically acceptable salt thereof. 8.A method of claim 7 wherein said compound is the hydrochloride saltthereof.
 9. A method for reducing serum cholesterol comprisingadministering to a patient in need of treatment an effective amount of acompound of formula I ##STR113## wherein R¹ is --H, --OH, --O(C₁ -C₄alkyl), --OCOC₆ H₅, --OCO(C₁ -C₆ alkyl), or --OSO₂ (C₂ -C₆ alkyl);R² is--H, --OH, --O(C₁ -C₄ alkyl), --OCOC₆ H₅, --OCO(C₁ -C₆ alkyl), --OSO₂(C₂ -C₆ alkyl) or halo; R³ is 1-piperidinyl, 1-pyrrolidinyl,methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino,dimethylamino, diethylamino, diisopropylamino, or 1-hexamethyleneimino;n is 2 or 3; and Z is --O-- or --S--;or a pharmaceutically acceptablesalt thereof.
 10. A method according to claim 9 wherein Z is --O--, n is2, and R³ is 1-piperidinyl, or a pharmaceutically acceptable saltthereof.
 11. A method according to claim 10 wherein R¹ and R² each are--O(C₁ -C₄ alkyl), or a pharmaceutically acceptable salt thereof.
 12. Amethod according to claim 11 wherein R¹ and R² each are --OCH₃, or apharmaceutically acceptable salt thereof.
 13. A method according toclaim 12 wherein said salt thereof is the hydrochloride salt.
 14. Amethod according to claim 9 wherein R¹ is --OH and R² is --O(C₁ -C₄alkyl), or a pharmaceutically acceptable salt thereof.
 15. A method forreducing serum cholesterol comprising administering to a patient in needof treatment an effective amount of a compound of the formula ##STR114##or a pharmaceutically acceptable salt thereof.
 16. A method of claim 15wherein said compound is the hydrochloride salt thereof.